Viewport Size Code:
Login | Create New Account


About | Classical Genetics | Timelines | What's New | What's Hot

About | Classical Genetics | Timelines | What's New | What's Hot


Bibliography Options Menu

Hide Abstracts   |   Hide Additional Links
Long bibliographies are displayed in blocks of 100 citations at a time. At the end of each block there is an option to load the next block.

Bibliography on: Telomeres

The Electronic Scholarly Publishing Project: Providing world-wide, free access to classic scientific papers and other scholarly materials, since 1993.


ESP: PubMed Auto Bibliography 08 Dec 2023 at 01:59 Created: 


Wikipedia: A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos (τέλος) "end" and merοs (μέρος, root: μερ-) "part". For vertebrates, the sequence of nucleotides in telomeres is TTAGGG, with the complementary DNA strand being AATCCC, with a single-stranded TTAGGG overhang. This sequence of TTAGGG is repeated approximately 2,500 times in humans. In humans, average telomere length declines from about 11 kilobases at birth to less than 4 kilobases in old age,[3] with average rate of decline being greater in men than in women. During chromosome replication, the enzymes that duplicate DNA cannot continue their duplication all the way to the end of a chromosome, so in each duplication the end of the chromosome is shortened (this is because the synthesis of Okazaki fragments requires RNA primers attaching ahead on the lagging strand). The telomeres are disposable buffers at the ends of chromosomes which are truncated during cell division; their presence protects the genes before them on the chromosome from being truncated instead. The telomeres themselves are protected by a complex of shelterin proteins, as well as by the RNA that telomeric DNA encodes.

Created with PubMed® Query: telomere.q.txt NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2023-12-01

Prévot D'Alvise N, Ascensio E, S Richard (2023)

Influence of EE2 exposure, age and sex on telomere length in European long-snouted seahorse (Hippocampus guttulatus).

General and comparative endocrinology pii:S0016-6480(23)00224-1 [Epub ahead of print].

After a Telomere Lengthening in juvenile stage, a progressive telomere shortening occurs with age despite higher telomerase level. Telomere Length (TL) may also reflect past physiological state such as a chronic chemical stress. Several studies have revealed a correlation between TL, ageing and/or sex in vertebrates, including teleosts; however, the patterns of telomere dynamics with telomerase mRNA expression, sex, lifespan or chemical stress in teleosts are unclear. The first aim of this study is to verify if telomere length is age and sex-dependent. The second aim is to consider if TL is a useful indicator of stress response in European long-snouted seahorse, Hippocampus guttulatus, an ectothermic and non-model system. We showed that after telomere lengthening during the juvenile stage, a telomeric attrition became significant in sexually mature individuals (p = 0.042). TL decreased in older seahorses despite the presence of somatic telomerase mRNA expression at all life stages studied. There was no difference in TL between males and females, but telomerase mRNA expression was consistently higher in females than males. Exposure to EE2 had no effect on TL in young seahorses, but was correlated with a significant increase in telomerase mRNA expression and various physiological disruptions. Here, a growth retardation of -10 % for body length (p = 0.016) and approximately -45 % for mass (p = 0.001) compared to healthy juvenile seahorses was observed. Our data suggest that telomere dynamics alone should not be used as a marker of EE2 exposure in juvenile seahorses.

RevDate: 2023-12-01

Zhang Y, Zhang C, Zhang C, et al (2023)

Leukocyte telomere length mediates the association between cadmium exposure and cognitive function in US older adults.

Journal of psychiatric research, 169:166-173 pii:S0022-3956(23)00532-0 [Epub ahead of print].

BACKGROUND: Long-term exposure to cadmium-polluted environments may lead to shortened leukocyte telomere length and cognitive decline. This study aims to investigate (1) the associations among blood cadmium levels, leukocyte telomere length, and cognitive function, and (2) the mediating role of leukocyte telomere length between blood cadmium levels and cognitive function among older adults in the United States.

METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Cadmium exposure level was assessed by measuring cadmium levels in blood samples. Leukocyte telomere length was measured by quantitative polymerase chain reaction, and cognitive function was measured by the digit symbol substitution test (DSST).

RESULTS: A total of 2185 older adults aged over 60 were included in this study, comprising 1109 (49.65%) males. Elevated blood cadmium levels were significantly associated with the risk of a decline in cognitive function (β = - 2.842, p = 0.018). Shorter leukocyte telomere lengths were significantly associated with a higher risk of a decline in cognitive function (β = 4.144, p = 0.020). The total indirect effect on the blood cadmium level and cognitive function via leukocyte telomere length was - 0.218 (p = 0.012). The mediation effect was estimated to be 0.218/2.084 × 100% = 10.46%.

CONCLUSION: The findings suggest that cadmium exposure may increase the risk of cognitive impairment by causing shortened leukocyte telomere length.

RevDate: 2023-12-04
CmpDate: 2023-12-04

Cottin V, M Kolb (2023)

Leukocyte telomere length: the dawn of a new era of personalised medicine in fibrotic interstitial lung diseases?.

The European respiratory journal, 62(5): pii:62/5/2301852.

RevDate: 2023-12-04
CmpDate: 2023-12-04

Bai C, Shen Z, Qiu B, et al (2023)

Leukocyte telomere length is associated with increased risk of endometriosis: a bidirectional two-sample Mendelian randomization study.

Frontiers in endocrinology, 14:1272200.

BACKGROUND: Endometriosis (EMs) is a common gynecological disorder. Observational studies on the relationship between leukocyte telomere length (LTL) and EMs have shown conflicting results. The purpose of this study was to evaluate the precise causal relationship between LTL and EMs using Mendelian randomization (MR) methodology.

METHODS: We employed MR to assess the causal relationship between LTL and EMs. Summary data from several large-scale genome-wide association studies (GWAS) were used for bidirectional two-sample MR analysis. Sensitivity analyses were conducted to ensure the robustness of our results. All analyses were also replicated in another completely independent EMs dataset.

RESULTS: Our MR analysis indicated that genetically predicted longer LTL increased the risk of EMs (IVW: discovery, OR=1.169, 95%CI: 1.059-1.290, p=0.002; validation, OR=1.302, 95%CI: 1.140-1.487, p=0.000), while EMs had no causal impact on LTL (IVW: discovery, OR=1.013, 95%CI: 1.000-1.027, p=0.056; IVW: validation, OR=1.005, 95%CI: 0.995-1.015, p=0.363). Causal estimates were supported by various calculation models (including MR-Egger, Weighted median, MR-PRESSO, and MR-RAPS). Heterogeneity and pleiotropy analyses also indicated robustness of the results.

CONCLUSION: Our findings substantiate the idea that a genetically predicted longer LTL elevates the risk of EMs, with no influence of EMs on LTL risk. This research bolsters the causal link between LTL and EMs, overcoming the constraints of earlier observational studies. It implies that LTL may potentially function as a biomarker for EMs, opening up novel possibilities for EMs prevention and treatment.

RevDate: 2023-12-01
CmpDate: 2023-12-01

Barcenilla BB, Meyers AD, Castillo-González C, et al (2023)

Arabidopsis telomerase takes off by uncoupling enzyme activity from telomere length maintenance in space.

Nature communications, 14(1):7854.

Spaceflight-induced changes in astronaut telomeres have garnered significant attention in recent years. While plants represent an essential component of future long-duration space travel, the impacts of spaceflight on plant telomeres and telomerase have not been examined. Here we report on the telomere dynamics of Arabidopsis thaliana grown aboard the International Space Station. We observe no changes in telomere length in space-flown Arabidopsis seedlings, despite a dramatic increase in telomerase activity (up to 150-fold in roots), as well as elevated genome oxidation. Ground-based follow up studies provide further evidence that telomerase is induced by different environmental stressors, but its activity is uncoupled from telomere length. Supporting this conclusion, genetically engineered super-telomerase lines with enhanced telomerase activity maintain wildtype telomere length. Finally, genome oxidation is inversely correlated with telomerase activity levels. We propose a redox protective capacity for Arabidopsis telomerase that may promote survivability in harsh environments.

RevDate: 2023-11-29

Zhou Q, Wang Y, Xin C, et al (2023)

Identification of telomere-associated gene signatures to predict prognosis and drug sensitivity in glioma.

Computers in biology and medicine, 168:107750 pii:S0010-4825(23)01215-5 [Epub ahead of print].

OBJECTIVE: Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties, leading to significant mortality and morbidity. Emerging evidence shows telomere maintenance has implicated in glioma susceptibility and prognosis. In this study, we comprehensively analyzed gene signatures related to telomere maintenance in glioma and their predictive values for predicting the prognosis and drug sensitivity in glioma.

METHODS: We initially identified telomere-related genes differentially expressed between low-grade glioma (LGG) and glioblastoma (GBM) and accordingly developed a risk model by univariate and multivariate Cox analysis to assess the expressions of telomere-related genes across the risk groups. Finally, to assess these genes in immune function the anti-tumor medications often used in the clinical treatment of glioma, we computed immune cell infiltration analysis and drug sensitivity analysis.

RESULTS: The consensus clustering analysis identified 20 telomere-related genes which split LGG patients into two distinct subtypes. The patient survival, the expressions of key telomere-related DEGs, and immune cell infiltration significantly differed between Cluster 1 and Cluster 2. The LASSO risk model [riskScore=(0.086)*HOXA7+(0.242)*WEE1+(0.247)*IGF2BP3+(0.052)*DUSP10] showed significant differences regarding the 1-, 3-, 5-year overall survival, immune cell infiltration, and drug sensitivity between high- and low-risk groups. The predictive nomogram constructed to quantify the survival probability of each sample at 1, 3, and 5 years was consistent with the actual patient survival.

CONCLUSION: Our comprehensive characterization of telomere-associated gene signatures in glioma reveals their possible roles in the development, tumor microenvironment, and prognosis. The study provides some suggestive relationships between four telomere-related genes (HOXA7, WEE1, IGF2BP3, and DUSP10) and glioma prognosis.

RevDate: 2023-11-29

Benites-Zapata VA, Ulloque-Badaracco JR, Alarcón-Braga EA, et al (2023)

Telomerase activity and telomere length in women with breast cancer or without malignancy: A systematic review and meta-analysis.

Maturitas, 180:107882 pii:S0378-5122(23)00488-7 [Epub ahead of print].

AIM: We performed a systematic review and meta-analysis to assess whether telomerase activity and telomere length are associated with breast cancer.

METHODS: PubMed, Web of Science, Embase, LILACS, Scielo, Embase, and CNKI databases were searched to obtain relevant articles published through May 10, 2023, following PRISMA guidelines and a registered PROSPERO protocol (CRD42022335402). We included observational studies reporting telomerase activity or telomere length in patients with breast cancer compared with women with benign lesions or normal tissue (control women). The Newcastle-Ottawa Scale was used to evaluate the quality of studies. Data were expressed as odds ratios (OR) and 95 % confidence intervals (CI). Random effects and inverse variance methods were used to meta-analyze associations. The I[2] test was used to assess heterogeneity.

RESULTS: The meta-analysis of telomerase shows significantly greater activity in patients with breast cancer than in those without malignancies (OR = 23.46, 95 % CI 14.07-39.11, p < 0.00001, I[2] = 72 %). There were non-significant differences in relative telomere length (OR = 1.16, 95 % CI = 0.90-1.49, p = 0.26, I[2] = 86 %) and leukocyte telomere length (OR = 2.32, 95 % CI = 0.89-6.08, p = 0.09, I[2] = 98 %) between women with and without breast cancer. In subgroup analyses by world regions of studies, both telomerase activity and telomere length displayed the same trends as in their respective meta-analyses. In sensitivity analyses, variables showed their respective same trends.

CONCLUSION: Telomerase activity is higher in patients with breast cancer than in women without malignancies. There were no significant differences in either relative telomere length or leukocyte telomere length in women with and without breast cancer. PROSPERO protocol CRD42022335402.

RevDate: 2023-11-29

Qin B (2023)

Can Antidiabetic Medications Affect Telomere Length in Patients with Type 2 Diabetes? A Mini-Review.

Diabetes, metabolic syndrome and obesity : targets and therapy, 16:3739-3750.

The fight against aging is an eternal pursuit of humankind. The aging rate of patients with type 2 diabetes mellitus (T2DM) is higher than that of healthy individuals. Reducing the aging rate of patients with T2DM and extending their life expectancy are challenges that endocrinologists are eager to overcome. Many studies have shown that antidiabetic medications have potent anti-aging potential. Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere shortening is a hallmark of aging. This review summarizes clinical trials that have explored the association between antidiabetic medications and telomere length (TL) in patients with T2DM and explore the mystery of delaying aging in patients with T2DM from the perspective of telomeres. Various antidiabetic medications may have different effects on TL in patients with T2DM. Metformin and sitagliptin may protect telomeres in patients with T2DM, while exogenous insulin may promote telomere shortening in patients with T2DM. The effect of acarbose and glyburide on TL in patients with T2DM is still uncertain due to the absence of evidence from longitudinal studies.

RevDate: 2023-11-29

Almuraikhy S, Sellami M, Al-Amri HS, et al (2023)

Impact of Moderate Physical Activity on Inflammatory Markers and Telomere Length in Sedentary and Moderately Active Individuals with Varied Insulin Sensitivity.

Journal of inflammation research, 16:5427-5438.

INTRODUCTION: Physical activity-associated immune response plays a crucial role in the aging process. This study aimed to determine the impact of short-term moderate physical activity on cytokine levels, oxidative stress markers, and telomere length in lean/overweight young subjects.

METHODS: Fasting blood samples were collected from 368 participants at Qatar Biobank. Based on their homeostatic model assessment of insulin resistance (HOMA-IR), participants were categorized as insulin sensitive (IS) or insulin resistant (IR). Subsequently, they were divided into four groups: sedentary IS (n = 90), sedentary IR (n = 90), moderately active IS (n = 94), and moderately active IR (n = 94). Moderate physical activity was defined as walking at least two days per week for more than 150 minutes, as determined by physical activity questionnaires. Serum samples were analyzed for circulating inflammatory cytokines (IL-1β, IL-1RA, IL-6, IL-10, IL-22, MCP-1/CCL2, TNF-α), as well as antioxidant enzyme levels (SOD and catalase). Telomere lengths were measured in the respective DNA samples.

RESULTS: Moderately active IR participants exhibited significantly lower SOD activity, while catalase activity did not show significant differences. Moderately active IS participants had higher IL-6 and IL-10 levels compared to sedentary IS participants, with no significant differences observed in the IR counterparts. Telomere length did not significantly differ between the physically active and sedentary groups.

CONCLUSION: This study highlights the potential anti-inflammatory and anti-oxidative stress effects of moderate physical activity in individuals with insulin sensitivity and insulin resistance. However, no significant changes in telomere length were observed, suggesting a complex relationship between physical activity and the aging process. Further research is needed to fully understand the underlying mechanisms and optimize the balance between anti-inflammation and anti-oxidation through exercise and lifestyle adjustments.

RevDate: 2023-11-29

Messerlian N, Zgheib N, Chokor FAZ, et al (2023)

Fructose intake and its association with relative telomere length: an exploratory study among healthy Lebanese adults.

Frontiers in nutrition, 10:1270124.

INTRODUCTION: Shorter relative telomere length (RTL) has been associated with increased incidence of morbidity. Although still disputed, available evidence suggests that dietary factors, including sugar-sweetened beverages (SSB) may be linked with shorter RTL. It was argued that the link between SSB and RTL may be explained by the sugar content of these beverages, and specifically fructose given its impact on oxidative stress and the inflammatory response. However, none of the existing studies have examined the specific link between fructose intake and RTL. This exploratory study aimed at (1) assessing the intake of dietary fructose (total, added and natural) in Lebanese healthy adults and (2) examining dietary fructose as a predictor of short telomere length.

METHODS: Following a cross-sectional design (n = 282), anthropometric and biochemical data were collected. RTL was assessed by utilizing real-time polymerase chain reaction (RT-qPCR) to amplify both telomere and single-copy gene segments. Dietary intake was evaluated using a culture-specific food frequency questionnaire (FFQ). Intakes of added fructose, naturally-occurring fructose, and total fructose were estimated.

RESULTS: Mean intakes of added and natural fructose were of 39.03 ± 34.12 and 12.28 ± 8.59 g/day, respectively, representing 4.80 ± 3.56 and 1.78 ± 1.41% of total energy intake (EI). Mean total fructose intake was of 51.31 ± 35.55 g/day, contributing 6.58 ± 3.71% EI. Higher intakes of total and added fructose were significantly associated with shorter RTL 2nd RTL tertile as compared to the 3rd RTL tertile; relative risk ratio (RRR) = 3.10 [95% confidence interval (CI): 1.38, 6.94] and RRR = 2.33 (95% CI: 1.02, 5.36), respectively after adjustment for confounders identified using a directed acyclic graph (DAG).

CONCLUSION: In conclusion, although we could not observe a dose-dependent relation between fructose intakes and RTL shortening and although the study is limited by its small sample size, the findings suggest that total and added dietary fructose intakes may be associated with shorter RTL. Larger studies, of longitudinal nature, are needed to further confirm the study findings.

RevDate: 2023-11-29

Wang L, Li LL, Chen L, et al (2023)

Telomere-to-telomere and haplotype-resolved genome assembly of the Chinese cork oak (Quercus variabilis).

Frontiers in plant science, 14:1290913.

The Quercus variabilis, a deciduous broadleaved tree species, holds significant ecological and economical value. While a chromosome-level genome for this species has been made available, it remains riddled with unanchored sequences and gaps. In this study, we present a nearly complete comprehensive telomere-to-telomere (T2T) and haplotype-resolved reference genome for Q. variabilis. This was achieved through the integration of ONT ultra-long reads, PacBio HiFi long reads, and Hi-C data. The resultant two haplotype genomes measure 789 Mb and 768 Mb in length, with a contig N50 of 65 Mb and 56 Mb, and were anchored to 12 allelic chromosomes. Within this T2T haplotype-resolved assembly, we predicted 36,830 and 36,370 protein-coding genes, with 95.9% and 96.0% functional annotation for each haplotype genome. The availability of the T2T and haplotype-resolved reference genome lays a solid foundation, not only for illustrating genome structure and functional genomics studies but also to inform and facilitate genetic breeding and improvement of cultivated Quercus species.

RevDate: 2023-11-29

Sun M, Yao C, Shu Q, et al (2023)

Telomere-to-telomere pear (Pyrus pyrifolia) reference genome reveals segmental and whole genome duplication driving genome evolution.

Horticulture research, 10(11):uhad201 pii:uhad201.

Previously released pear genomes contain a plethora of gaps and unanchored genetic regions. Here, we report a telomere-to-telomere (T2T) gap-free genome for the red-skinned pear, 'Yunhong No. 1' (YH1; Pyrus pyrifolia), which is mainly cultivated in Yunnan Province (southwest China), the pear's primary region of origin. The YH1 genome is 501.20 Mb long with a contig N50 length of 29.26 Mb. All 17 chromosomes were assembled to the T2T level with 34 characterized telomeres. The 17 centromeres were predicted and mainly consist of centromeric-specific monomers (CEN198) and long terminal repeat (LTR) Gypsy elements (≥74.73%). By filling all unclosed gaps, the integrity of YH1 is markedly improved over previous P. pyrifolia genomes ('Cuiguan' and 'Nijisseiki'). A total of 1531 segmental duplication (SD) driven duplicated genes were identified and enriched in stress response pathways. Intrachromosomal SDs drove the expansion of disease resistance genes, suggesting the potential of SDs in adaptive pear evolution. A large proportion of duplicated gene pairs exhibit dosage effects or sub-/neo-functionalization, which may affect agronomic traits like stone cell content, sugar content, and fruit skin russet. Furthermore, as core regulators of anthocyanin biosynthesis, we found that MYB10 and MYB114 underwent various gene duplication events. Multiple copies of MYB10 and MYB114 displayed obvious dosage effects, indicating role differentiation in the formation of red-skinned pear fruit. In summary, the T2T gap-free pear genome provides invaluable resources for genome evolution and functional genomics.

RevDate: 2023-11-29

Xu XD, Zhao RP, Xiao L, et al (2023)

Telomere-to-telomere assembly of cassava genome reveals the evolution of cassava and divergence of allelic expression.

Horticulture research, 10(11):uhad200 pii:uhad200.

Cassava is a crucial crop that makes a significant contribution to ensuring human food security. However, high-quality telomere-to-telomere cassava genomes have not been available up to now, which has restricted the progress of haploid molecular breeding for cassava. In this study, we constructed two nearly complete haploid resolved genomes and an integrated, telomere-to-telomere gap-free reference genome of an excellent cassava variety, 'Xinxuan 048', thereby providing a new high-quality genomic resource. Furthermore, the evolutionary history of several species within the Euphorbiaceae family was revealed. Through comparative analysis of haploid genomes, it was found that two haploid genomes had extensive differences in linear structure, transcriptome features, and epigenetic characteristics. Genes located within the highly divergent regions and differentially expressed alleles are enriched in the functions of auxin response and the starch synthesis pathway. The high heterozygosity of cassava 'Xinxuan 048' leads to rapid trait segregation in the first selfed generation. This study provides a theoretical basis and genomic resource for molecular breeding of cassava haploids.

RevDate: 2023-11-29

Zeng T, He Z, He J, et al (2023)

The telomere-to-telomere gap-free reference genome of wild blueberry (Vaccinium duclouxii) provides its high soluble sugar and anthocyanin accumulation.

Horticulture research, 10(11):uhad209 pii:uhad209.

Vaccinium duclouxii, endemic to southwestern China, is a berry-producing shrub or small tree belonging to the Ericaceae family, with high nutritive, medicinal, and ornamental value, abundant germplasm resources, and good edible properties. In addition, V. duclouxii exhibits strong tolerance to adverse environmental conditions, making it a promising candidate for research and offering wide-ranging possibilities for utilization. However, the lack of V. duclouxii genome sequence has hampered its development and utilization. Here, a high-quality telomere-to-telomere genome sequence of V. duclouxii was de novo assembled and annotated. All of 12 chromosomes were assembled into gap-free single contigs, providing the highest integrity and quality assembly reported so far for blueberry. The V. duclouxii genome is 573.67 Mb, which encodes 41 953 protein-coding genes. Combining transcriptomics and metabolomics analyses, we have uncovered the molecular mechanisms involved in sugar and acid accumulation and anthocyanin biosynthesis in V. duclouxii. This provides essential molecular information for further research on the quality of V. duclouxii. Moreover, the high-quality telomere-to-telomere assembly of the V. duclouxii genome will provide insights into the genomic evolution of Vaccinium and support advancements in blueberry genetics and molecular breeding.

RevDate: 2023-11-29

Farrukh S, S Baig (2023)

Parental telomeres implications on immune senescence of newborns.

American journal of clinical and experimental immunology, 12(5):81-86.

Telomere, the biological chronometer, and its effect on the immune system considerably varies among individuals. During pregnancy, multiple risk factors affect telomere reprogramming during fetal life which can lead to health disparities in newborns. These changes may cause a long-term impact on the telomere genetics of the newborn and become a reason for lifelong health implications and immune senescence. Therefore, telomere shortening in parents due to genetic variation may act as a hallmark of immune senescence and aging in their newborns.

RevDate: 2023-11-29

Srikanth P, Chowdhury AR, Low GKM, et al (2022)

Oxidative Damage Induced Telomere Mediated Genomic Instability in Cells from Ataxia Telangiectasia Patients.

Genome integrity, 13:2 pii:genint.13.1.003.

Our cellular genome is susceptible to cytotoxic lesions which include single strand breaks and double strand breaks among other lesions. Ataxia telangiectasia mutated (ATM) protein was one of the first DNA damage sensor proteins to be discovered as being involved in DNA repair and as well as in telomere maintenance. Telomeres help maintain the stability of our chromosomes by protecting the ends from degradation. Cells from ataxia telangiectasia (AT) patients lack ATM and accumulate chromosomal alterations. AT patients display heightened susceptibility to cancer. In this study, cells from AT patients (called as AT [-/-] and AT [+/-] cells) were characterized for genome stability status and it was observed that AT [-/-] cells show considerable telomere attrition. Furthermore, DNA damage and genomic instability were compared between normal (AT [+/+] cells) and AT [-/-] cells exhibiting increased frequencies of spontaneous DNA damage and genomic instability markers. Both AT [-/-] and AT [+/-] cells were sensitive to sodium arsenite (1.5 and 3.0 μg/ml) and ionizing radiation-induced (2 Gy, gamma rays) oxidative stress. Interestingly, telomeric fragments were detected in the comet tails as revealed by comet-fluorescence in situ hybridization analysis, suggestive of telomeric instability in AT [-/-] cells upon exposure to sodium arsenite or radiation. Besides, there was an increase in the number of chromosome alterations in AT [-/-] cells following arsenite treatment or irradiation. In addition, complex chromosome aberrations were detected by multicolor fluorescence in situ hybridization in AT [-/-] cells in comparison to AT [+/-] and normal cells. Telomere attrition and chromosome alterations were detected even at lower doses of sodium arsenite. Peptide nucleic acid - FISH analysis revealed defective chromosome segregation in cells lacking ATM proteins. The data obtained in this study substantiates the role of ATM in telomere stability under oxidative stress.

RevDate: 2023-11-29

Fernández-Álvarez A (2023)

Beyond tradition: exploring the non-canonical functions of telomeres in meiosis.

Frontiers in cell and developmental biology, 11:1278571 pii:1278571.

The telomere bouquet is a specific chromosomal configuration that forms during meiosis at the zygotene stage, when telomeres cluster together at the nuclear envelope. This clustering allows cytoskeleton-induced movements to be transmitted to the chromosomes, thereby facilitating homologous chromosome search and pairing. However, loss of the bouquet results in more severe meiotic defects than can be attributed solely to recombination problems, suggesting that the bouquet's full function remains elusive. Despite its transient nature and the challenges in performing in vivo analyses, information is emerging that points to a remarkable suite of non-canonical functions carried out by the bouquet. Here, we describe how new approaches in quantitative cell biology can contribute to establishing the molecular basis of the full function and plasticity of the bouquet, and thus generate a comprehensive picture of the telomeric control of meiosis.

RevDate: 2023-11-29

Balouchi M, Huang SH, McGrath SL, et al (2023)

The telomere resolvase, TelA, utilizes an underwound pre-cleavage intermediate to promote hairpin telomere formation.

PloS one, 18(11):e0294732 pii:PONE-D-23-27013.

The telomere resolvase, TelA, forms the hairpin telomeres of the linear chromosome of Agrobacterium tumefaciens in a process referred to as telomere resolution. Telomere resolution is a unique DNA cleavage and rejoining reaction that resolves replicated telomere junctions into a pair of hairpin telomeres. Telomere resolvases utilize a reaction mechanism with similarities to that of topoisomerase-IB enzymes and tyrosine recombinases. The reaction proceeds without the need for high-energy cofactors due to the use of a covalent, enzyme-cleaved DNA intermediate that stores the bond energy of the cleaved bonds in 3'-phosphotyrosyl linkages. The cleaved DNA strands are then refolded into a hairpin conformation and the 5'-OH ends of the refolded strands attack the 3'-phosphotyrosine linkages in order to rejoin the DNA strands into hairpin telomeres. Because this kind of reaction mechanism is, in principle, reversible it is unclear how TelA controls the direction of the reaction and propels the reaction to completion. We present evidence that TelA forms and/or stabilizes a pre-cleavage intermediate that features breakage of the four central basepairs between the scissile phosphates prior to DNA cleavage to help propel the reaction forwards, thus preventing abortive cleavage and rejoining cycles that regenerate the substrate DNA. We identify eight TelA sidechains, located in the hairpin-binding module and catalytic domains of TelA, implicated in this process. These mutants were deficient for telomere resolution on parental replicated telomere junctions but were rescued by introduction of substrate modifications that mimic unwinding of the DNA between the scissile phosphates.

RevDate: 2023-11-29

Mostafa H, Gutierrez-Tordera L, Mateu-Fabregat J, et al (2023)

Dietary fat, telomere length and cognitive function: unravelling the complex relations.

Current opinion in lipidology [Epub ahead of print].

PURPOSE OF REVIEW: The review aims to explore the recent evidence on the associations between different dietary fat intake and cognitive function, and to understand the role of telomere length in this relationship.

RECENT FINDINGS: Clinical and preclinical studies included in this review suggest that dietary fat intake is associated with cognitive function and telomere length. High intake of saturated fats and trans fats, commonly found in ultra-processed foods, appears to have negative effects on cognitive function and telomere length, while other dietary fats, such as omega-3 polyunsaturated fatty acids and monounsaturated fatty acids are associated with improved cognitive performance and reduced telomere attrition. Controversial results related to omega-6 polyunsaturated fatty acids intake and its impact on cognitive function were found. Dietary fats may affect telomere length and cognition through oxidative stress, inflammation, and insulin resistance.

SUMMARY: The current review illustrated the relationship between dietary fat and cognitive function by focusing on the role of telomere length as a potential intermediator. More future studies are required, however, in order to develop targeted interventions aimed at preserving cognitive well-being throughout life.

RevDate: 2023-11-28

Le Bras A (2023)

Short telomeres in Telomice.

Lab animal pii:10.1038/s41684-023-01297-9 [Epub ahead of print].

RevDate: 2023-11-28

Valipour B, Davari S, Farahzadi R, et al (2023)

Inhibition of mitochondria induces apoptosis and reduces telomere length and activity in acute myeloid leukemia stem cells.

Cell biochemistry and function [Epub ahead of print].

Acute myeloid leukemia (AML) is a highly lethal hematological malignancy in adults and children. Abnormal proliferation of leukemia stem cells (LSC) with CD34[+] and CD38[-] phenotypes are the main clinical features of AML. Patients with AML face drug resistance and treatment failure due to a default in stem and progenitor cells. Therefore, defining LSC properties is necessary for targeting leukemia-initiating cells. Mitochondrial mass and activity increase in AML initiating cells compared with normal stem cells. This idea has offered the inhibition of the mitochondrial translation machinery to reduce the number of leukemia-initiating cells in patients with AML Tigecycline is an FDA-approved microbial antibiotic that inhibits oxidative phosphorylation in mitochondria, resulting in the suppression of leukemia cell proliferation with little toxicity to normal cells. Thus, the present study was conducted to evaluate whether LSC is influenced by mitochondrial inhibition. We measured the IC50 of tigecycline in KG-1a AML cell lines. KG-1a AML cell lines were separated into CD34[+] and CD34[-] cells by MACS. In the following, these cells were treated with 20 µM (IC50) tigecycline. The expression of Annexin/PI, Caspase 3, apoptotic genes (BCL2, BCLX, BAX, BAD, and P53) and proteins (P53, BAX, BCL2 and Caspase 9) was evaluated in CD34[+] , CD34[-] and KG-1a AML cells. In addition, the telomere length and expression of hTERT were evaluated in this study. The results indicated that BCl2 (gene and protein) and BCLX gene dramatically decreased. In addition, BAD, BAX, and P53 gene and protein expression significantly increased in CD34[+] AML cells compared to CD34[-] AML cells. The results also suggested that tigecycline induced intrinsic (Cleaved-caspase 9/Pro-Caspase 9 ratio) and p53-mediated apoptosis. Furthermore, hTERT gene expression and telomere length decreased in the tigecycline-treated groups. Taken together, our findings indicate that inhibition of mitochondrial activity with tigecycline can induce apoptosis in cancer stem cells and can be used as a novel method for cancer therapy.

RevDate: 2023-11-29
CmpDate: 2023-11-28

San-Cristobal R, de Toro-Martín J, Guénard F, et al (2023)

Impact of maternal cardiometabolic status after bariatric surgery on the association between telomere length and adiposity in offspring.

Scientific reports, 13(1):20771.

The impact of bariatric surgery on metabolic and inflammatory status are reflected in the epigenetic profile and telomere length mediated by the changes in the metabolic status of the patients. This study compared the telomere length of children born before versus after maternal bariatric surgery as a surrogate to test the influence of the mother's metabolic status on children's telomere length. DNA methylation telomere length (DNAmTL) was estimated from Methylation-EPIC BeadChip array data from a total of 24 children born before and after maternal bariatric surgery in the greater Quebec City area. DNAmTL was inversely associated with chronological age in children (r = - 0.80, p < 0.001) and significant differences were observed on age-adjusted DNAmTL between children born before versus after the maternal bariatric surgery. The associations found between body mass index and body fat percentage with DNAmTL in children born after the surgery were influenced by maternal triglycerides, TG/HDL-C ratio and TyG index. This study reports the impact of maternal bariatric surgery on offspring telomere length. The influence of maternal metabolic status on the association between telomere length and markers of adiposity in children suggests a putative modulating effect of bariatric surgery on the cardiometabolic risk in offspring.

RevDate: 2023-11-28
CmpDate: 2023-11-28

Yu TN, Cheng EH, Lin YP, et al (2023)

Significantly shortened telomere length and altered androgen receptor level in cumulus cells from women with polycystic ovary syndrome.

Taiwanese journal of obstetrics & gynecology, 62(6):845-851.

OBJECTIVE: The aim of this study was to investigate the correlation between hormone receptor levels and telomere length (TL) in infertile women with and without polycystic ovary syndrome (PCOS).

MATERIALS AND METHODS: This prospective cohort study recruited a total of 431 cumulus oocyte complex (COC) from 88 infertile women between July 2012 and June 2014. The participants were divided into three groups: young age (<38 years, n = 42 and 227 COC), advanced age (≥38 years, n = 33 and 107 COC) and PCOS patients (n = 13 and 97 COC). Cumulus cells were collected from individual follicle during oocyte pick-up, and the mRNA levels of hormone receptors and TL were measured using real-time PCR.

RESULTS: The cumulus cells of PCOS patients demonstrated lower mRNA levels of LH receptor (75.57 ± 138.10 vs. 171.07 ± 317.68; p < 0.01) and androgen receptor (1.13 ± 1.52 vs. 4.08 ± 9.57; p < 0.01), as well as a shorter TL (2.39 ± 2.58 vs. 3.96 ± 4.72; p < 0.01) compared to those of the young age group. In the young age group, only androgen receptor mRNA level showed a significant association with TL (rho = 0.148, p = 0.026), while FSH receptor mRNA level was the only factor associated with TL (rho = 0.247, p = 0.015) in PCOS patients. For advanced-aged patients, no significant relationship was observed between hormone receptor mRNA levels and TL. Alternative splicing of androgen receptors was identified in some PCOS patients but not in young age controls.

CONCLUSION: The findings suggest that the androgen receptor level and function may be altered in the cumulus cells of PCOS patients, leading to a shorter TL in cumulus cells in PCOS patients.

RevDate: 2023-11-27
CmpDate: 2023-11-27

Tao Y, He C, Lin D, et al (2023)

Comprehensive Identification of Mitochondrial Pseudogenes (NUMTs) in the Human Telomere-to-Telomere Reference Genome.

Genes, 14(11):.

Practices related to mitochondrial research have long been hindered by the presence of mitochondrial pseudogenes within the nuclear genome (NUMTs). Even though partially assembled human reference genomes like hg38 have included NUMTs compilation, the exhaustive NUMTs within the only complete reference genome (T2T-CHR13) remain unknown. Here, we comprehensively identified the fixed NUMTs within the reference genome using human pan-mitogenome (HPMT) from GeneBank. The inclusion of HPMT serves the purpose of establishing an authentic mitochondrial DNA (mtDNA) mutational spectrum for the identification of NUMTs, distinguishing it from the polymorphic variations found in NUMTs. Using HPMT, we identified approximately 10% of additional NUMTs in three human reference genomes under stricter thresholds. And we also observed an approximate 6% increase in NUMTs in T2T-CHR13 compared to hg38, including NUMTs on the short arms of chromosomes 13, 14, and 15 that were not assembled previously. Furthermore, alignments based on 20-mer from mtDNA suggested the presence of more mtDNA-like short segments within the nuclear genome, which should be avoided for short amplicon or cell free mtDNA detection. Finally, through the assay of transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) on cell lines before and after mtDNA elimination, we concluded that NUMTs have a minimal impact on bulk ATAC-seq, even though 16% of sequencing data originated from mtDNA.

RevDate: 2023-11-28

Coltell O, Asensio EM, Sorlí JV, et al (2023)

Associations between the New DNA-Methylation-Based Telomere Length Estimator, the Mediterranean Diet and Genetics in a Spanish Population at High Cardiovascular Risk.

Antioxidants (Basel, Switzerland), 12(11):.

Biological aging is a relevant risk factor for chronic diseases, and several indicators for measuring this factor have been proposed, with telomere length (TL) among the most studied. Oxidative stress may regulate telomere shortening, which is implicated in the increased risk. Using a novel estimator for TL, we examined whether adherence to the Mediterranean diet (MedDiet), a highly antioxidant-rich dietary pattern, is associated with longer TL. We determined TL using DNA methylation algorithms (DNAmTL) in 414 subjects at high cardiovascular risk from Spain. Adherence to the MedDiet was assessed by a validated score, and genetic variants in candidate genes and at the genome-wide level were analyzed. We observed several significant associations (p < 0.05) between DNAmTL and candidate genes (TERT, TERF2, RTEL1, and DCAF4), contributing to the validity of DNAmTL as a biomarker in this population. Higher adherence to the MedDiet was associated with lower odds of having a shorter TL in the whole sample (OR = 0.93; 95% CI: 0.85-0.99; p = 0.049 after fully multivariate adjustment). Nevertheless, this association was stronger in women than in men. Likewise, in women, we observed a direct association between adherence to the MedDiet score and DNAmTL as a continuous variable (beta = 0.015; SE: 0.005; p = 0.003), indicating that a one-point increase in adherence was related to an average increase of 0.015 ± 0.005 kb in TL. Upon examination of specific dietary items within the global score, we found that fruits, fish, "sofrito", and whole grains exhibited the strongest associations in women. The novel score combining these items was significantly associated in the whole population. In the genome-wide association study (GWAS), we identified ten polymorphisms at the suggestive level of significance (p < 1 × 10[-5]) for DNAmTL (intergenics, in the IQSEC1, NCAPG2, and ABI3BP genes) and detected some gene-MedDiet modulations on DNAmTL. As this is the first study analyzing the DNAmTL estimator, genetics, and modulation by the MedDiet, more studies are needed to confirm these findings.

RevDate: 2023-11-24

Qi M, Yu J, Ping F, et al (2023)

Leukocyte telomere length independently predicts hyperuricemia risk in a longitudinal study of the Chinese population.

Nutrition, metabolism, and cardiovascular diseases : NMCD pii:S0939-4753(23)00407-6 [Epub ahead of print].

BACKGROUND AND AIMS: Leukocyte telomere length (LTL) has been correlated with uric acid levels, although results are inconsistent, and prospective studies are lacking. In this longitudinal, prospective cohort study, we aimed to assess whether a shorter LTL predicts the risk of hyperuricemia.

METHODS AND RESULTS: We conducted a longitudinal study in a Chinese cohort of 599 participants. Of these, 266 participants completed a 5.9-year follow-up from June 2014 to December 2021. LTL was assessed at baseline using real-time polymerase chain reaction. Hyperuricemia was defined as serum uric acid ≥420 mmol/L according to Chinese guidelines for diagnosis and treatment of hyperuricemia and gout. Participants who had developed hyperuricemia during follow-up (n = 17) had shorter LTL at baseline. Baseline LTL was independently associated with the development of hyperuricemia at follow-up after adjusting for conventional hyperuricemia risk factors (odds ratio [OR] 2.347 [95% confidence interval [CI] 1.123, 4.906]; P = 0.023). After grouping according to LTL tertiles, the incidence of hyperuricemia was 18.334-fold higher for the first than for the third tertile (OR 18.334 [95%CI 1.786, 191.272]; P = 0.014, P for trend = 0.050).

CONCLUSION: Our findings in a prospective cohort suggest that LTL could predict hyperuricemia risk, which might inform the timely prevention and treatment of hyperuricemia.

RevDate: 2023-11-26

Zhang N, Baker EC, Welsh TH, et al (2023)

Telomere Dynamics in Livestock.

Biology, 12(11):.

Telomeres are repeated sequences of nucleotides at the end of chromosomes. They deteriorate across mitotic divisions of a cell. In Homo sapiens this process of lifetime reduction has been shown to correspond with aspects of organismal aging and exposure to stress or other insults. The early impetus to characterize telomere dynamics in livestock related to the concern that aged donor DNA would result in earlier cell senescence and overall aging in cloned animals. Telomere length investigations in dairy cows included breed effects, estimates of additive genetic control (heritability 0.12 to 0.46), and effects of external stressors on telomere degradation across animal life. Evaluation of telomeres with respect to aging has also been conducted in pigs and horses, and there are fewer reports of telomere biology in beef cattle, sheep, and goats. There were minimal associations of telomere length with animal productivity measures. Most, but not all, work in livestock has documented an inverse relationship between peripheral blood cell telomere length and age; that is, a longer telomere length was associated with younger age. Because livestock longevity affects productivity and profitability, the role of tissue-specific telomere attrition in aging may present alternative improvement strategies for genetic improvement while also providing translational biomedical knowledge.

RevDate: 2023-11-24

Park S, DK Kim (2023)

Comment on 'Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia' by Park et al. - The authors reply.

RevDate: 2023-11-23

Setia N, Del Gaudio D, Kandikatla P, et al (2023)

A novel telomere biology disease-associated gastritis identified through a whole exome sequencing-driven approach.

The journal of pathology. Clinical research [Epub ahead of print].

A whole exome sequencing (WES)-driven approach to uncover the etiology of unexplained inflammatory gastritides has been underutilized by surgical pathologists. Here, we discovered the pathobiology of an unusual chronic atrophic gastritis in two unrelated patients using this approach. The gastric biopsies were notable for an unusual pattern of gastritis with persistent dense inflammation, loss of both parietal and neuroendocrine cells in the oxyntic mucosa, and sparing of the antral mucosa. The patients were found to harbor pathogenic variants in telomeropathic genes (POT1 and DCLRE1B). Clonality testing for one of the patients showed evidence of evolving clonality of TCR-gene rearrangement. Both patients showed significantly decreased numbers of stem/progenitor cells by immunohistochemistry, which appears to be responsible for the development of mucosal atrophy. No such cases of unusual chronic atrophic gastritis in the setting of telomeropathy have been previously reported. The loss of stem/progenitor cells suggests that stem/progenitor cell exhaustion in the setting of telomere dysfunction is the likely mechanism for development of this unusual chronic atrophic gastritis. The results underscore the need for close monitoring of these gastric lesions, with special regard to their neoplastic potential. This combined WES-driven approach has promise to identify the cause and mechanism of other uncharacterized gastrointestinal inflammatory disorders.

RevDate: 2023-11-22

Robinson LG, Kalmbach K, Sumerfield O, et al (2023)

Telomere Dynamics and Reproduction.

Fertility and sterility pii:S0015-0282(23)02001-0 [Epub ahead of print].

The oocyte, a long-lived, post-mitotic cell, is the locus of reproductive aging in women. Female germ cells replicate only during fetal life and age throughout reproductive life. Mechanisms of oocyte aging include accumulation of oxidative damage, mitochondrial dysfunction and disruption of proteins, including cohesion. Nobel Laureate Bob Edwards also discovered a "production line" during oogonial replication in the mouse, wherein the last oocytes to ovulate in the adult derived from the last oogonia to exit mitotic replication in the fetus. Based on this, we proposed a two hit "telomere theory of reproductive aging" to integrate the myriad features of oocyte aging. The first hit- oocytes remaining in older women traversed more cell cycles during fetal oogenesis. The second hit- oocytes accumulated more environmental and endogenous oxidative damage across the life of the woman. Telomeres could mediate both these aspects of oocyte aging. Telomeres provide a "mitotic clock", with telomere attrition an inevitable consequence of cell division due to of the end-replication problem. And telomere's guanine-rich sequence renders them especially sensitive to oxidative damage, even in post-mitotic cells. Telomerase, the reverse transcriptase that restores telomeres, is better at maintaining than elongating telomeres. Moreover, telomerase remains inactive during much of oogenesis and early development. Oocytes are left with short telomeres, on the brink of viability. In support of this theory, mice with induced telomere attrition and women with naturally occurring telomeropathy suffer diminished ovarian reserve, abnormal embryo development and infertility. In contrast, sperm are produced throughout the life of the male by a telomerase-active progenitor, spermatogonia, resulting in the longest telomeres in the body. In mice, cleavage stage embryos elongate telomeres via "Alternative Lengthening of Telomeres (ALT)", a recombination-based mechanism, rarely encountered outside of telomerase-deficient cancers. Many questions about telomeres and reproduction are raised by these findings:- Does the "normal" telomere attrition observed in human oocytes contribute to their extraordinarily high rate of meiotic non-disjunction? Does recombination-based telomere elongation render embryos susceptible to mitotic non-disjunction (and mosaicism)? Can some features of telomeres serve as markers of oocyte quality?

RevDate: 2023-11-22

Wang C, Huang Y, Yang Y, et al (2023)

ILF3 safeguards telomeres from aberrant homologous recombination as a telomeric R-loop reader.

Protein & cell pii:7441334 [Epub ahead of print].

Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability. The telomeric repeat-containing RNA (TERRA) that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called R-loop. In tumor cells, R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres (ALT) pathway. Dysregulated R-loops can cause stalled replication forks and telomere instability. However, how R-loops are recognized and regulated, particularly at telomeres, is not well understood. We discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous recombination. Knocking out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage responses (DDR). In addition, ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT pathway. Using the proximity-dependent biotin identification (BioID) technology, we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases, including DHX9. Importantly, ILF3 may aid in the resolution of telomeric R-loops through its interaction with DHX9. Our findings suggest that ILF3 may function as a reader of telomeric R-loops, helping to prevent abnormal homologous recombination and maintain telomere homeostasis.

RevDate: 2023-11-24
CmpDate: 2023-11-23

Colin L, Reyes C, Berthezene J, et al (2023)

Condensin positioning at telomeres by shelterin proteins drives sister-telomere disjunction in anaphase.

eLife, 12:.

The localization of condensin along chromosomes is crucial for their accurate segregation in anaphase. Condensin is enriched at telomeres but how and for what purpose had remained elusive. Here, we show that fission yeast condensin accumulates at telomere repeats through the balancing acts of Taz1, a core component of the shelterin complex that ensures telomeric functions, and Mit1, a nucleosome remodeler associated with shelterin. We further show that condensin takes part in sister-telomere separation in anaphase, and that this event can be uncoupled from the prior separation of chromosome arms, implying a telomere-specific separation mechanism. Consistent with a cis-acting process, increasing or decreasing condensin occupancy specifically at telomeres modifies accordingly the efficiency of their separation in anaphase. Genetic evidence suggests that condensin promotes sister-telomere separation by counteracting cohesin. Thus, our results reveal a shelterin-based mechanism that enriches condensin at telomeres to drive in cis their separation during mitosis.

RevDate: 2023-11-21

Harley J, Santosa MM, Ng CY, et al (2023)

Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes.

Biogerontology [Epub ahead of print].

Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining the length of telomeres, which are specialised protective caps at the end of chromosomes. The lack of in vitro aging models, particularly for the central nervous system (CNS), has impeded progress in understanding aging and age-associated neurodegenerative diseases. In this study, we aimed to explore the possibility of inducing aging-associated features in cell types of the CNS using hiPSC (human induced pluripotent stem cell) technology. To achieve this, we utilised CRISPR/Cas9 to generate hiPSCs with a loss of telomerase function and shortened telomeres. Through directed differentiation, we generated motor neurons and astrocytes to investigate whether telomere shortening could lead to age-associated phenotypes. Our findings revealed that shortened telomeres induced age-associated characteristics in both motor neurons and astrocytes including increased cellular senescence, heightened inflammation, and elevated DNA damage. We also observed cell-type specific age-related morphology changes. Additionally, our study highlighted the fundamental role of TERT and telomere shortening in neural progenitor cell (NPC) proliferation and neuronal differentiation. This study serves as a proof of concept that telomere shortening can effectively induce aging-associated phenotypes, thereby providing a valuable tool to investigate age-related decline and neurodegenerative diseases.

RevDate: 2023-11-21

Pierpoint M, Floyd W, Wisdom AJ, et al (2023)

Loss of function of Atrx leads to activation of alternative lengthening of telomeres in a primary mouse model of sarcoma.

bioRxiv : the preprint server for biology pii:2023.11.06.565874.

The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of telomeres (ALT). In this work, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice which displays multiple molecular features of ALT activation after CRISPR/Cas9 introduction of oncogenic Kras [G12D] and loss of function mutations of Trp53 and Atrx. In this model, we demonstrate that the loss of Atrx contributes to the development of ALT in an autochthonous tumor, and this process occurs independently of telomerase function by variation of mTR alleles. Furthermore, we find that telomere shortening from the loss of telomerase leads to higher chromosomal instability while loss of Atrx and activation of ALT lead to an increase in telomeric instability, telomere sister chromatid exchange, c-circle production, and formation of ALT-associated promyelocytic leukemia bodies (APBs). The development of this primary mouse model of ALT could enable future investigations into therapeutic vulnerabilities of ALT activation and its mechanism of action.

RevDate: 2023-11-21

Zhang W (2023)

Big data analysis identified a telomere-related signature predicting the prognosis and drug sensitivity in lung adenocarcinoma.

Medicine, 102(46):e35526.

Telomeres exert a critical role in chromosome stability and aberrant regulation of telomerase may result in telomeres dysfunction and genomic instability, which are involved in the occurrence of cancers. However, limited studies have been performed to fully clarify the immune infiltration and clinical significance of telomeres-related genes (TRGs) in lung adenocarcinoma (LUAD). The number of clusters of LUAD was determined by consensus clustering analysis. The prognostic signature was constructed and verified using TCGA and GSE42127 dataset with Least Absolute Shrinkage and Selection Operator cox regression analysis. The correlation between different clusters and risk-score and drug therapy response was analyzed using TIDE and IMvigor210 dataset. Using several miRNA and lncRNA related databases, we constructed a lncRNA-miRNA-mRNA regulatory axis. We identified 2 telomeres-related clusters in LUAD, which had distinct differences in prognostic stratification, TMB score, TIDE score, immune characteristics and signal pathways and biological effects. A prognostic model was developed based on 21 TRGs, which had a better performance in risk stratification and prognosis prediction compared with other established models. TRGs-based risk score could serve as an independent risk factor for LUAD. Survival prediction nomogram was also developed to promote the clinical use of TRGs risk score. Moreover, LUAD patients with high risk score had a high TMB score, low TIDE score and IC50 value of common drugs, suggesting that high risk score group might benefit from receiving immunotherapy, chemotherapy and target therapy. We also developed a lncRNA KCNQ1QT1/miR-296-5p/PLK1 regulatory axis. Our study identified 2 telomeres-related clusters and a prognostic model in LUAD, which could be helpful for risk stratification, prognosis prediction and treatment approach selection.

RevDate: 2023-11-21

Li W, Liu C, Chen Y, et al (2023)

Assessment of the relationship between telomere length and atherosclerosis: A Mendelian randomization study.

Medicine, 102(46):e35875.

To evaluate the causal relationship between genetically determined telomere length (TL) and atherosclerosis (AS). We performed a 2-sample Mendelian randomization (MR) study to assess the potential causal relationship between TL and AS (coronary AS, cerebral AS, peripheral atherosclerosis (PAD), and AS, excluding cerebral, coronary, and PAD). The TL phenotype contained 472,174 participants, and the 4 subtypes of AS had 361,194, 218,792, 168,832, and 213,140 participants, all of European ancestries. The single nucleotide polymorphisms (SNPs) of TL strongly associated with the 4 atherosclerotic subtypes included in this study were 101, 92, 91, and 92, respectively. The odds ratios (ORs) and 95% confidence interval (CI) between TL and coronary AS calculated using inverse variance weighted (IVW) were 0.993 (0.988, 0.997), and the results were statistically significant (P < .05). The results between TL and cerebral AS, PAD, and AS (excluding cerebral, coronary, and PAD) were not statistically significant (P > .05). "Egger-intercept test" showed that there was no horizontal pleiotropy (P > .05); "leave-one-out analysis" sensitivity analysis showed that the results were stable and there were no instrumental variables with strong effects on the results; "MR- pleiotropy residual sum and outlier (PRESSO) test" showed 1 outlier for coronary AS and no outliers for the remaining subgroups. The results of the 2-sample MR analysis showed a causal association between TL and coronary AS but not with cerebral AS, PAD, and AS (excluding cerebral, coronary, and PAD). This may elucidate the observation that various vascular regions can be affected by AS but highlights the propensity of coronary arteries to be more susceptible to AS development.

RevDate: 2023-11-21

Serrano-León IM, Prieto P, M Aguilar (2023)

Correction: Telomere and subtelomere high polymorphism might contribute to the specifcity of homologous recognition and pairing during meiosis in barley in the context of breeding.

BMC genomics, 24(1):694.

RevDate: 2023-11-20

Mulet A, González-Cabo P, Pallardó FV, et al (2023)

Persistent Pulmonary Fibrotic Sequelae in Patients With Telomere Shortening One Year After Severe COVID-19.

RevDate: 2023-11-20

Schmidt KA, DA Simonetto (2023)

The telomere Tango: Liver disease in the Genomic spotlight.

Hepatology (Baltimore, Md.) pii:01515467-990000000-00659 [Epub ahead of print].

RevDate: 2023-11-18

Garg A, E Seli (2023)

Leukocyte telomere length and DNA methylome as biomarkers of ovarian reserve and embryo aneuploidy: The intricate relationship between somatic and reproductive aging.

Fertility and sterility pii:S0015-0282(23)02000-9 [Epub ahead of print].

The average childbearing age amongst women continues to rise, leading to an increased prevalence of infertility and a subsequent increased use of assisted reproductive technologies (ART). Ovarian aging, especially diminished ovarian reserve (DOR) and poor ovarian response (POR) have been implicated as common causes of infertility. Telomere length and DNA methylation-based epigenetic clocks are established hallmarks of cellular aging, however, the interplay between somatic and ovarian aging remains unclear. There appears to be a lack of correlation between leukocyte telomere length and DNA methylation age of somatic and ovarian cells. Both the telomere length and methylome of follicular somatic cells (granulosa and cumulus) appear to be unaffected by chronologic age, infertility, or processes that result in DOR/POR. As such they are unlikely candidates as surrogate biomarkers of reproductive potential, response to stimulation, or ART outcome. On the other hand, telomere or methylome changes in leukocytes associated with aging seem to correlate with reproductive function and may have the potential to aid the characterization of women with reproductive decline, however, current data is limited and larger studies evaluating this within an ART setting are warranted.

RevDate: 2023-11-20

Liu L, Luo H, Sheng Y, et al (2023)

A novel mutation of CTC1 leads to telomere shortening in a chinese family with interstitial lung disease.

Hereditas, 160(1):37.

Interstitial lung diseases (ILDs), or diffuse pulmonary lung disease, are a subset of lung diseases that primarily affect lung alveoli and the space around interstitial tissue and bronchioles. It clinically manifests as progressive dyspnea, and patients often exhibit a varied decrease in pulmonary diffusion function. Recently, variants in telomere biology-related genes have been identified as genetic lesions of ILDs. Here, we enrolled 82 patients with interstitial pneumonia from 2017 to 2021 in our hospital to explore the candidate gene mutations of these patients via whole-exome sequencing. After data filtering, a novel heterozygous mutation (NM_025099: p.Gly131Arg) of CTC1 was identified in two affected family members. As a component of CST (CTC1-STN1-TEN1) complex, CTC1 is responsible for maintaining telomeric structure integrity and has also been identified as a candidate gene for IPF, a special kind of chronic ILD with insidious onset. Simultaneously, real-time PCR revealed that two affected family members presented with short telomere lengths, which further confirmed the effect of the mutation in the CTC1 gene. Our study not only expanded the mutation spectrum of CTC1 and provided epidemiological data on ILDs caused by CTC1 mutations but also further confirmed the relationship between heterozygous mutations in CTC1 and ILDs, which may further contribute to understanding the mechanisms underlying ILDs.

RevDate: 2023-11-17

Campa D, Felici A, Corradi C, et al (2023)

Long or short? Telomere length and pancreatic cancer and its precursor lesions, a narrative review.

Mutagenesis pii:7425608 [Epub ahead of print].

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, with a survival approaching only 11% at five years after diagnosis. In the last 15 years, telomere length measured in leukocyte (LTL) has been studied in relation to PDAC risk. The majority of the studies reported an association between short LTL and increased PDAC risk, but the results are heterogeneous. Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) gene as susceptibility loci for PDAC. Polygenic risk scores (PRS) computed using SNPs associated with LTL have been tested in relation to PDAC susceptibility with various methods and giving contrasting results. The aim of this review is to analyze all publications carried out specifically on LTL, considering LTL measured with qPCR and with genetic proxies, and PDAC risk. Additionally, we will give an overview of the most relevant associations between SNPs in telomere associated genes and PDAC, to answer the question shorter or longer? Which one of the two is associated with PDAC risk?

RevDate: 2023-11-17

Zhao Z, Shen X, Zhao S, et al (2023)

A novel telomere-related genes model for predicting prognosis and treatment responsiveness in diffuse large B-cell lymphoma.

Aging, 15: pii:205211 [Epub ahead of print].

Diffuse large B cell lymphoma (DLBCL) is a highly heterogeneous disease with diverse clinical and molecular features. Telomere maintenance is widely present in tumors, but there is a lack of relevant reports on the role of telomere-related genes (TRGs) in DLBCL. In this study, we used consensus clustering based on TRGs expression to identify two molecular clusters with distinct prognoses and immune cell infiltration. We developed a TRGs scoring model using univariate Cox regression and LASSO regression in the GSE10846 training cohort. DLBCL patients in the high-risk group had a worse prognosis than those in the low-risk group, as revealed by Kaplan-Meier curves. The scoring model was validated in the GSE10846 testing cohort and GSE87371 cohort, respectively. The high-risk group was characterized by elevated infiltration of activated DCs, CD56 dim natural killer cells, myeloid-derived suppressor cells, monocytes, and plasmacytoid DCs, along with reduced infiltration of activated CD4 T cells, Type 2 T helper cells, γδ T cells, NK cells, and neutrophils. Overexpression of immune checkpoints, such as PDCD1, CD274, and LAG3, was observed in the high-risk group. Furthermore, high-risk DLBCL patients exhibited increased sensitivity to bortezomib, rapamycin, AZD6244, and BMS.536924, while low-risk DLBCL patients showed sensitivity to cisplatin and ABT.263. Using RT-qPCR, we found that three protective model genes, namely TCEAL7, EPHA4, and ELOVL4, were down-regulated in DLBCL tissues compared with control tissues. In conclusion, our novel TRGs-based model has great predictive value for the prognosis of DLBCL patients and provides a promising direction for treatment optimization.

RevDate: 2023-11-17

Tomé S (2023)

[Nanopore and telomeres].

Medecine sciences : M/S, 39 Hors série n° 1:64.

RevDate: 2023-11-16

Anonymous (2023)

Boyraz B, Bellomo CM, Fleming MD, Cutler CS, Agarwal S. A novel TERC CR4/CR5 domain mutation causes telomere disease via decreased TERT binding. Blood. 2016;128(16):2089-2092.

Blood, 142(20):1758.

RevDate: 2023-11-16

Khaleda L, Begum SK, Apu MAR, et al (2023)

Arsenic-Induced Cardiovascular Diseases and their Correlation with Mitochondrial DNA Copy Number, Deletion, and Telomere Length in Bangladeshi Population.

Cardiovascular toxicology [Epub ahead of print].

Arsenic contamination is a global health concern, primarily through contaminated groundwater and its entry into the food chain. The association between arsenic exposure and cardiovascular diseases (CVDs) is particularly alarming due to CVDs being the leading cause of death worldwide. Arsenic exposure has also been linked to changes in telomere length, mitochondrial DNA copy number (mtDNAcn), and deletion, further increasing the risk of CVDs. We aimed to determine whether arsenic exposure alters telomere length and mtDNAcn and deletion in a total of 50 CVD patients who underwent open heart surgery hailed from known arsenic-affected and unaffected areas in Bangladesh. Amount of arsenic was determined from the collected nails and cardiac tissues. Relative telomere length and mtDNAcn and deletion were quantified by qRT-PCR. The patients from arsenic-contaminated areas had higher average arsenic deposits in their fingers and toenails (P < 0.05) and higher cardiac tissue injury scores (P < 0.05). Moreover, approximately 1.5-fold shorter telomere length (P < 0.05, r = - 0.775), 1.2-fold decreased mtDNAcn (P < 0.05, r = - 0.797), and an 81-fold higher amount of mitochondrial DNA deletion (P < 0.05, r = 0.784) were observed in the patients who had higher arsenic deposition in their nails. Higher levels of arsenic exposure were found to be linked to shorter telomere length, decreased mtDNAcn, and increased mitochondrial DNA deletion in the patients from As-affected areas. It can also be anticipated that the correlation of arsenic exposure with telomere length, mtDNAcn, and deletion can be used as biomarkers for early diagnosis of arsenic-induced cardiovascular diseases.

RevDate: 2023-11-15

Zavala-Paez M, Holliday J, JA Hamilton (2023)

Leveraging whole-genome sequencing to estimate telomere length in plants.

Molecular ecology resources [Epub ahead of print].

Changes in telomere length are increasingly used to indicate species' response to environmental stress across diverse taxa. Despite this broad use, few studies have explored telomere length in plants. Thus, evaluation of new approaches for measuring telomeres in plants is needed. Rapid advances in sequencing approaches and bioinformatic tools now allow estimation of telomere content from whole-genome sequencing (WGS) data, a proxy for telomere length. While telomere content has been quantified extensively using quantitative polymerase chain reaction (qPCR) and WGS in humans, no study to date has compared the effectiveness of WGS in estimating telomere length in plants relative to qPCR approaches. In this study, we use 100 Populus clones re-sequenced using short-read Illumina sequencing to quantify telomere length comparing three different bioinformatic approaches (Computel, K-seek and TRIP) in addition to qPCR. Overall, telomere length estimates varied across different bioinformatic approaches, but were highly correlated across methods for individual genotypes. A positive correlation was observed between WGS estimates and qPCR, however, Computel estimates exhibited the greatest correlation. Computel incorporates genome coverage into telomere length calculations, suggesting that genome coverage is likely important to telomere length quantification when using WGS data. Overall, telomere estimates from WGS provided greater precision and accuracy of telomere length estimates relative to qPCR. The findings suggest WGS is a promising approach for assessing telomere length and, as the field of telomere ecology evolves, may provide added value to assaying response to biotic and abiotic environments for plants needed to accelerate plant breeding and conservation management.

RevDate: 2023-11-15

Kmiołek T, Filipowicz G, Bogucka D, et al (2023)

Aging and the impact of global DNA methylation, telomere shortening, and total oxidative status on sarcopenia and frailty syndrome.

Immunity & ageing : I & A, 20(1):61.

Aging is a biological event that influences many organs and systems. Both sarcopenia and frailty syndrome refer to geriatric conditions with overlapping phenotypes. Many mechanisms are involved in the aging process such as DNA methylation telomeres which are susceptible to oxidative stress, and inflammations which result in telomere shortening, leading to chromosomal instability. The study aimed to determine the associations between these processes, frailty and sarcopenia syndrome. Global DNA methylation was analyzed using the ELISA method. Telomere length was analyzed using qPCR. Total oxidative status (TOS) was analyzed using a colorimetric method. The present study revealed that the main factor affecting methylation, telomeres length and level of total oxidant stress was age.

RevDate: 2023-11-14

Liang Y, P Huang (2023)

Associations of telomere length with risk of mortality from influenza and pneumonia in US adults: a prospective cohort study of NHANES 1999-2002.

Aging clinical and experimental research [Epub ahead of print].

BACKGROUND: Due to the ongoing Coronavirus disease 2019 (COVID-19) pandemic, interest has arisen to realize the relationship between telomere length (TL) and influenza and pneumonia mortality.

AIM: Our study attempted to investigate this correlation by analyzing information gathered from the National Health and Nutrition Examination Survey (NHANES) 1999-2002.

METHODS: A total of 7229 participants were involved in the conducted research. We utilized Cox proportional risk model analysis to determine the hazard ratio (HR) and 95% confidence interval (CI) for TL and influenza and pneumonia mortality.

RESULTS: During the average follow-up time of 204.10 ± 51.26 months, 33 (0.45%) participants died from influenza and pneumonia. After adjusting for multiple variables, shorter TL was associated with higher influenza-pneumonia mortality. In subgroup analyses stratified by sex, men exhibited stronger associations with influenza-pneumonia mortality than women (Model 1: HRmale: 0.014 vs HRfemale: 0.054; Model 2: HRmale: 0.082 vs HRfemale: 0.890; Model 3: HRmale: 0.072 vs HRfemale: 0.776). For subgroup analyses by visceral adiposity index (VAI), all statistically significant (P < 0.05) models displayed an inverse relationship between TL and influenza and pneumonia mortality.

CONCLUSIONS: Our research provides further proof for the connection between shorter telomeres and higher influenza-pneumonia mortality. Larger prospective researches are essential to support our results and explain the underlying mechanisms.

RevDate: 2023-11-14

Gold NM, Okeke MN, Y He (2023)

Involvement of Inheritance in Determining Telomere Length beyond Environmental and Lifestyle Factors.

Aging and disease pii:AD.2023.1023 [Epub ahead of print].

All linear chromosomal ends have specific DNA-protein complexes called telomeres. Telomeres serve as a "molecular clock" to estimate the potential length of cell replication. Shortening of telomere length (TL) is associated with cellular senescence, aging, and various age-related diseases in humans. Here we reviewed the structure, function, and regulation of telomeres and the age-related diseases associated with telomere attrition. Among the various determinants of TL, we highlight the connection between TL and heredity to provide a new overview of genetic determinants for TL. Studies across multiple species have shown that maternal and paternal TL influence the TL of their offspring, and this may affect life span and their susceptibility to age-related diseases. Hence, we reviewed the linkage between TL and parental influences and the proposed mechanisms involved. More in-depth studies on the genetic mechanism for TL attrition are needed due to the potential application of this knowledge in human medicine to prevent premature frailty at its earliest stage, as well as promote health and longevity.

RevDate: 2023-11-14

Takai H, Aria V, Borges P, et al (2023)

CST-Polymeraseα-primase solves a second telomere end-replication problem.

bioRxiv : the preprint server for biology pii:2023.10.26.564248.

Telomerase solves the end-replication problem by adding G-rich telomeric repeats to the 3' ends of telomeres [1] . We report a second end-replication problem affecting the C-rich telomeric repeat strand that is solved by fill-in synthesis by CST-Polymeraseα(Polα)-primase. In vitro replication of linear DNAs showed that lagging-strand DNA synthesis stops >40 nt before the replisome reaches the 5' end of the template. Incomplete lagging-strand DNA synthesis is predicted to result in progressive shortening of the telomeric C-strand. Two assays to measure C-strand shortening at telomere ends in telomerase-deficient cells lacking the Ctc1 subunit of CST-Polα-primase revealed that lagging-end telomeres lose C-strand sequences at ∼60 nt/population doubling (PD), consistent with the in vitro replication data. The C-strands of leading-end telomeres shortened by ∼108 nt/PD, consistent with resection converting the blunt ends to 3' overhangs. The overall shortening rate of the C-rich telomeric strand in Ctc1-deficient cells was consistent with the combined effects of incomplete lagging-strand synthesis and 5' end resection at the leading-ends. We conclude that canonical DNA replication creates two telomere end-replication problems that require telomerase to maintain the G-rich strand and CST-Polα-primase to maintain the C-rich strand.

RevDate: 2023-11-14

Agabekian IA, Abdulkina LR, Lushnenko AY, et al (2023)

Arabidopsis AN3 and OLIGOCELLULA genes link telomere maintenance mechanisms with cell division and expansion control.

Research square

Telomeres are conserved chromosomal structures necessary for continued cell division and proliferation. In addition to the classical telomerase pathway, multiple other genes including those involved in ribosome metabolism and chromatin modification contribute to telomere length maintenance. We previously reported that Arabidopsis thaliana ribosome biogenesis genes OLI2/NOP2A, OLI5/RPL5A and OLI7/RPL5B have critical roles in telomere length regulation. These three OLIGOCELLULA genes were also shown to function in cell proliferation and expansion control and to genetically interact with the transcriptional co-activator ANGUSTIFOLIA3 (AN3). Here we show that AN3- deficient plants progressively lose telomeric DNA in early homozygous mutant generations, but ultimately establish a new shorter telomere length setpoint by the fifth mutant generation with a telomere length similar to oli2/nop2a -deficient plants. Analysis of double an3 oli2 mutants indicates that the two genes are epistatic for telomere length control. Telomere shortening in an3 and oli mutants is not caused by telomerase inhibition; wild type levels of telomerase activity are detected in all analyzed mutants in vitro . Late generations of an3 and oli mutants are prone to stem cell damage in the root apical meristem, implying that genes regulating telomere length may have conserved functional roles in stem cell maintenance mechanisms. Multiple instances of anaphase fusions in late generations of oli5 and oli7 mutants were observed, highlighting an unexpected effect of ribosome biogenesis factors on chromosome integrity. Overall, our data implicate AN3 transcription coactivator and OLIGOCELLULA proteins in the establishment of telomere length set point in plants and further suggest that multiple regulators with pleiotropic functions can connect telomere biology with cell proliferation and cell expansion pathways.

RevDate: 2023-11-14

Xing B, Yu J, Liu Y, et al (2023)

High Dietary Zinc Intake Is Associated with Shorter Leukocyte Telomere Length, Mediated by Tumor Necrosis Factor-α: A Study of China Adults.

The journal of nutrition, health & aging, 27(10):904-910.

OBJECTIVES: Diet can influence peripheral leukocyte telomere length (LTL), and various micronutrients have been reported to correlate with it. Zinc is known for its antioxidant properties and immunomodulatory effects. However, there are few epidemiological investigations on the relationship between dietary zinc intake and LTL. This study analyzed the association between dietary zinc and LTL and the potential role of inflammation and oxidative stress among them.

DESIGN: Cross-sectional and community-based study.

SETTING AND PARTICIPANTS: 599 participants from rural communities in the Changping suburb of Beijing, China, were recruited.

MEASUREMENTS: Serum lipid profile, glycosylated hemoglobin (HbA1c), oxidative stress marker, and inflammatory cytokines levels were measured. Detailed dietary data were obtained using a 24 h food recall. LTL was assessed using a real-time PCR assay. Spearman analysis, restricted cubic splines (RCS), and general linear regression models were used to determine the association between dietary zinc intake and LTL. Simple regulatory models were also applied to analyze the role of inflammation and oxidative stress among them.

RESULTS: A total of 482 subjects were ultimately included in this analysis. Spearman analysis showed that dietary zinc intake and zinc intake under energy density were negatively correlated with LTL (r=-0.142 and -0.126, all P <0.05) and positively correlated with tumor necrosis factor-α (TNF-α) (r=0.138 and 0.202, all P <0.05) while only dietary zinc without energy adjustment had a positive correlation with superoxide dismutase (SOD). RCS (P for non-linearity=0.933) and multiple linear regression (B=-0.084, P=0.009) indicated a negative linear association between dietary zinc and LTL. The adjustment of TNF-α rather than SOD could abolish the relationship. The mediation model suggested that the unfavorable effect of dietary zinc on LTL was mediated by TNF-α.

CONCLUSIONS: High dietary zinc may correlate with telomere attrition, and TNF-α can act as a mediator in this relationship. In the future, more extensive cohort studies are needed to further explore the relationship between dietary zinc and cellular aging and the specific mechanisms.

RevDate: 2023-11-14

Zhu G, Xu J, Guo G, et al (2023)

Association between Lipids, Apolipoproteins and Telomere Length: A Mendelian Randomization Study.

Nutrients, 15(21): pii:nu15214497.

(1) Background: The relationship between lipids, apolipoproteins, and telomere length (TL) has been explored in previous studies; however, the causal relationship between the two remains unclear. This study aims to assess the causal relationship between lipids, apolipoproteins, and TL using the two-sample Mendelian randomization (MR) approach; (2) Methods: This study comprehensively employed both univariate MR (uvMR) and multivariate MR (mvMR) methods to genetically evaluate the associations between 21 exposures related to lipids and apolipoproteins and the outcome of TL. During the analysis process, we utilized various statistical methods, including Inverse Variance Weighting (IVW), Weighted Median, MR-Egger regression, MR-PRESSO, and outlier tests. Furthermore, to confirm the robustness of the results, we conducted several sensitivity analyses to explore potential heterogeneity; (3) Results: The uvMR analysis indicated that an increase in MUFA, MUFA/FA ratio, LDL-C, VLDL-C, total cholesterol, ApoB, and triglycerides (TG) was associated with an increase in TL. However, this relationship did not manifest in the mvMR analysis, suggesting that this association may be based on preliminary evidence; (4) Conclusions: MR analysis results suggest potential suggestive positive causal relationships between genetically predicted MUFA, MUFA/FA ratio, LDL-C, VLDL-C, total cholesterol, ApoB, and TG with TL.

RevDate: 2023-11-14

Kalmykova A (2023)

Telomere Checkpoint in Development and Aging.

International journal of molecular sciences, 24(21): pii:ijms242115979.

The maintenance of genome integrity through generations is largely determined by the stability of telomeres. Increasing evidence suggests that telomere dysfunction may trigger changes in cell fate, independently of telomere length. Telomeric multiple tandem repeats are potentially highly recombinogenic. Heterochromatin formation, transcriptional repression, the suppression of homologous recombination and chromosome end protection are all required for telomere stability. Genetic and epigenetic defects affecting telomere homeostasis may cause length-independent internal telomeric DNA damage. Growing evidence, including that based on Drosophila research, points to a telomere checkpoint mechanism that coordinates cell fate with telomere state. According to this scenario, telomeres, irrespective of their length, serve as a primary sensor of genome instability that is capable of triggering cell death or developmental arrest. Telomeric factors released from shortened or dysfunctional telomeres are thought to mediate these processes. Here, we discuss a novel signaling role for telomeric RNAs in cell fate and early development. Telomere checkpoint ensures genome stability in multicellular organisms but aggravates the aging process, promoting the accumulation of damaged and senescent cells.

RevDate: 2023-11-14

Grzeczka A, Graczyk S, P Kordowitzki (2023)

DNA Methylation and Telomeres-Their Impact on the Occurrence of Atrial Fibrillation during Cardiac Aging.

International journal of molecular sciences, 24(21): pii:ijms242115699.

Atrial fibrillation (AF) is the most common arrhythmia in humans. AF is characterized by irregular and increased atrial muscle activation. This high-frequency activation obliterates the synchronous work of the atria and ventricles, reducing myocardial performance, which can lead to severe heart failure or stroke. The risk of developing atrial fibrillation depends largely on the patient's history. Cardiovascular diseases are considered aging-related pathologies; therefore, deciphering the role of telomeres and DNA methylation (mDNA), two hallmarks of aging, is likely to contribute to a better understanding and prophylaxis of AF. In honor of Prof. Elizabeth Blackburn's 75th birthday, we dedicate this review to the discovery of telomeres and her contribution to research on aging.

RevDate: 2023-11-14

Rodriguez-Martin I, Villanueva-Martin G, Guillen-Del-Castillo A, et al (2023)

Contribution of Telomere Length to Systemic Sclerosis Onset: A Mendelian Randomization Study.

International journal of molecular sciences, 24(21): pii:ijms242115589.

Although previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528-0.970], p = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563-0.911], p = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the TERC and TERT genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc.

RevDate: 2023-11-13

Lu X, L Liu (2023)

Genome stability from the perspective of telomere length.

Trends in genetics : TIG pii:S0168-9525(23)00241-X [Epub ahead of print].

Telomeres and their associated proteins protect the ends of chromosomes to maintain genome stability. Telomeres undergo progressive shortening with each cell division in mammalian somatic cells without telomerase, resulting in genome instability. When telomeres reach a critically short length or are recognized as a damage signal, cells enter a state of senescence, followed by cell cycle arrest, programmed cell death, or immortalization. This review provides an overview of recent advances in the intricate relationship between telomeres and genome instability. Alongside well-established mechanisms such as chromosomal fusion and telomere fusion, we will delve into the perspective on genome stability by examining the role of retrotransposons. Retrotransposons represent an emerging pathway to regulate genome stability through their interactions with telomeres.

RevDate: 2023-11-12

Carvalho Borges PC, Bouabboune C, Escandell JM, et al (2023)

Pot1 promotes telomere DNA replication via the Stn1-Ten1 complex in fission yeast.

Nucleic acids research pii:7416369 [Epub ahead of print].

Telomeres are nucleoprotein complexes that protect the chromosome-ends from eliciting DNA repair while ensuring their complete duplication. Pot1 is a subunit of telomere capping complex that binds to the G-rich overhang and inhibits the activation of DNA damage checkpoints. In this study, we explore new functions of fission yeast Pot1 by using a pot1-1 temperature sensitive mutant. We show that pot1 inactivation impairs telomere DNA replication resulting in the accumulation of ssDNA leading to the complete loss of telomeric DNA. Recruitment of Stn1 to telomeres, an auxiliary factor of DNA lagging strand synthesis, is reduced in pot1-1 mutants and overexpression of Stn1 rescues loss of telomeres and cell viability at restrictive temperature. We propose that Pot1 plays a crucial function in telomere DNA replication by recruiting Stn1-Ten1 and Polα-primase complex to telomeres via Tpz1, thus promoting lagging-strand DNA synthesis at stalled replication forks.

RevDate: 2023-11-11

Banaszak LG, Smith-Simmer K, Shoger K, et al (2023)

Implementation of a prospective screening strategy to identify adults with a telomere biology disorder among those undergoing lung transplant evaluation for interstitial lung disease.

Respiratory medicine pii:S0954-6111(23)00352-9 [Epub ahead of print].

INTRODUCTION: Patients with interstitial lung disease (ILD) secondary to telomere biology disorders (TBD) experience increased morbidity after lung transplantation. Identifying patients with TBD may allow for personalized management to facilitate better outcomes. However, establishing a TBD diagnosis in adults is challenging.

METHODS: A TBD screening questionnaire was introduced prospectively into the lung transplant evaluation. Patients with ILD screening positive were referred for comprehensive TBD phenotyping and concurrent telomere length measurement and germline genetic testing.

RESULTS: Of 98 patients, 32 (33%) screened positive. Eight patients (8% of total; 25% of patients with a positive screen) met strict TBD diagnostic criteria, requiring either critically short lymphocyte telomeres (<1st percentile) (n = 4), a pathogenic variant in a TBD-associated gene (n = 1), or both (n = 3) along with a TBD clinical phenotype. Additional patients not meeting strict diagnostic criteria had histories consistent with TBD along with telomere lengths <10th percentile and/or rare variants in TBD-associated genes, highlighting a critical need to refine TBD diagnostic criteria for this patient population.

CONCLUSION: A TBD phenotype screening questionnaire in patients with ILD undergoing lung transplant evaluation has a diagnostic yield of 25%. Additional gene discovery, rare variant functional testing, and refined TBD diagnostic criteria are needed to realize the maximum benefit of testing for TBD in patients undergoing lung transplantation.

RevDate: 2023-11-11

Nassour J, Przetocka S, J Karlseder (2023)

Telomeres as hotspots for innate immunity and inflammation.

DNA repair, 133:103591 pii:S1568-7864(23)00145-3 [Epub ahead of print].

Aging is marked by the gradual accumulation of deleterious changes that disrupt organ function, creating an altered physiological state that is permissive for the onset of prevalent human diseases. While the exact mechanisms governing aging remain a subject of ongoing research, there are several cellular and molecular hallmarks that contribute to this biological process. This review focuses on two factors, namely telomere dysfunction and inflammation, which have emerged as crucial contributors to the aging process. We aim to discuss the mechanistic connections between these two distinct hallmarks and provide compelling evidence highlighting the loss of telomere protection as a driver of pro-inflammatory states associated with aging. By reevaluating the interplay between telomeres, innate immunity, and inflammation, we present novel perspectives on the etiology of aging and its associated diseases.

RevDate: 2023-11-13
CmpDate: 2023-11-13

Hassanpour H, Mirshokraei P, Salehpour M, et al (2023)

Canine sperm motility is associated with telomere shortening and changes in expression of shelterin genes.

BMC veterinary research, 19(1):236.

BACKGROUND: Motion quality is a critical property for essential functions. Several endogenous and exogenous factors are involved in sperm motility. Here, we measured the relative telomere length and evaluated the gene expression of its binding-proteins, shelterin complex (TRF1, TRF2, RAP1, POT1, TIN2, and TPP1) in sperm of dogs using relative quantitative real-time PCR. We compared them between two sperm subpopulations with poor and good motion qualities (separated by swim-up method). Telomere shortening and alterations of shelterin gene expression result from ROS, genotoxic insults, and genetic predisposition.

RESULTS: Sperm kinematic parameters were measured in two subpopulations and then telomeric index of each parameter was calculated. Telomeric index for linearity, VSL, VCL, STR, BCF, and ALH were significantly higher in sperms with good motion quality than in sperms with poor quality. We demonstrated that poor motion quality is associated with shorter telomere, higher expression of TRF2, POT1, and TIN2 genes, and lower expression of the RAP1 gene in dog sperm. The levels of TRF1 and TPP1 gene expression remained consistent despite variations in sperm quality and telomere length.

CONCLUSION: Data provided evidence that there are considerable changes in gene expression of many shelterin components (TRF2, TIN2, POT1and RAP1) associated with shortening telomere in the spermatozoa with poor motion quality. Possibly, the poor motion quality is the result of defects in the shelterin complex and telomere length. Our data suggests a new approach in the semen assessment and etiologic investigations of subfertility or infertility in male animals.

RevDate: 2023-11-10

Randell Z, Dehghanbanadaki H, Fendereski K, et al (2023)

Sperm Telomere Length in Male-Factor Infertility and Reproduction.

Fertility and sterility pii:S0015-0282(23)01990-8 [Epub ahead of print].

RevDate: 2023-11-10

Ferrer A, Stephens ZD, JA Kocher (2023)

Experimental and Computational Approaches to Measure Telomere Length: Recent Advances and Future Directions.

Current hematologic malignancy reports [Epub ahead of print].

PURPOSE OF REVIEW: The length of telomeres, protective structures at the chromosome ends, is a well-established biomarker for pathological conditions including multisystemic syndromes called telomere biology disorders. Approaches to measure telomere length (TL) differ on whether they estimate average, distribution, or chromosome-specific TL, and each presents their own advantages and limitations.

RECENT FINDINGS: The development of long-read sequencing and publication of the telomere-to-telomere human genome reference has allowed for scalable and high-resolution TL estimation in pre-existing sequencing datasets but is still impractical as a dedicated TL test. As sequencing costs continue to fall and strategies for selectively enriching telomere regions prior to sequencing improve, these approaches may become a promising alternative to classic methods. Measurement methods rely on probe hybridization, qPCR or more recently, computational methods using sequencing data. Refinements of existing techniques and new approaches have been recently developed but a test that is accurate, simple, and scalable is still lacking.

RevDate: 2023-11-11

Yan J, Jin T, L Wang (2023)

Hematopoietic stem cell transplantation of aplastic anemia by relative with mutations and normal telomere length: A case report.

World journal of clinical cases, 11(29):7200-7206.

BACKGROUND: Immunosuppressive therapy and matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) are the preferred treatments for aplastic anemia (AA).

CASE SUMMARY: In this report, we describe a 43-year-old male patient with severe AA who carried BRIP1 (also known as FANCJ), TINF2, and TCIRG1 mutations. Screening of the family pedigree revealed the same TINF2 mutation in his mother and older brother, with his older brother also carrying the BRIP1 variant and demonstrating normal telomere length and hematopoietic function. The patient was successfully treated with oral cyclosporine A, eltrombopag, and acetylcysteine, achieving remission 4 years after receiving MSD-HSCT from his older brother.

CONCLUSION: This case provides a valuable clinical reference for individuals with suspected pathogenic gene mutations, normal telomere length, and hematopoietic function, highlighting them as potential donors for patients with AA.

RevDate: 2023-11-11

Rolles B, Caballero-Oteyza A, Proietti M, et al (2023)

Telomere biology disorders may manifest as common variable immunodeficiency (CVID).

Clinical immunology (Orlando, Fla.), 257:109837 pii:S1521-6616(23)00600-9 [Epub ahead of print].

Telomere biology disorders (TBD) are caused by germline pathogenic variants in genes related to telomere maintenance and are characterized by critically short telomeres. In contrast to classical dyskeratosis congenita (DC), which is typically diagnosed in infancy, adult or late onset TBD frequently lack the typical DC triad and rather show variable organ manifestations and a cryptic disease course, thus complicating its diagnosis. Common variable immunodeficiency (CVID), on the other hand, is a primary antibody deficiency (PAD) syndrome. PADs are a heterogenous group of diseases characterized by hypogammaglobulinemia which occurs due to dysfunctional B lymphocytes and additional autoimmune and autoinflammatory complications. Genetic screening reveals a monogenic cause in a subset of CVID patients (15-35%). In our study, we screened the exomes of 491 CVID patients for the occurrence of TBD-related variants in 13 genes encoding for telomere/telomerase-associated proteins, which had previously been linked to the disease. We found 110/491 patients (22%) carrying 91 rare candidate variants in these 13 genes. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified two variants as benign, two as likely benign, 64 as variants of uncertain significance (VUS), four as likely pathogenic, and one heterozygous variant in an autosomal recessive disease gene as pathogenic. We performed telomere length measurement in 42 of the 110 patients with candidate variants and CVID. Two of these 42 patients showed significantly shorter telomeres compared to controls in both lymphocytes and granulocytes. Following the evaluation of the published literature and the patient's manifestations, we re-classified two VUS as likely pathogenic variants. Thus, 0.5-1% of all CVID patients in our study carry possibly pathogenic variants in telomere/telomerase-associated genes. Our data adds CVID to the broad clinical spectrum of cryptic adult-onset TBD. As the molecular diagnosis greatly impacts patient management and treatment strategies, we advise inclusion of all TBD-associated genes-despite their low prevalence-into the molecular screening of patients with antibody deficiencies.

RevDate: 2023-11-11
CmpDate: 2023-11-10

Sato MP, Iwakami S, Fukunishi K, et al (2023)

Telomere-to-telomere genome assembly of an allotetraploid pernicious weed, Echinochloa phyllopogon.

DNA research : an international journal for rapid publication of reports on genes and genomes, 30(5):.

Echinochloa phyllopogon is an allotetraploid pernicious weed species found in rice fields worldwide that often exhibit resistance to multiple herbicides. An accurate genome sequence is essential to comprehensively understand the genetic basis underlying the traits of this species. Here, the telomere-to-telomere genome sequence of E. phyllopogon was presented. Eighteen chromosome sequences spanning 1.0 Gb were constructed using the PacBio highly fidelity long technology. Of the 18 chromosomes, 12 sequences were entirely assembled into telomere-to-telomere and gap-free contigs, whereas the remaining six sequences were constructed at the chromosomal level with only eight gaps. The sequences were assigned to the A and B genome with total lengths of 453 and 520 Mb, respectively. Repetitive sequences occupied 42.93% of the A genome and 48.47% of the B genome, although 32,337, and 30,889 high-confidence genes were predicted in the A and B genomes, respectively. This suggested that genome extensions and gene disruptions caused by repeated sequence accumulation often occur in the B genome before polyploidization to establish a tetraploid genome. The highly accurate and comprehensive genome sequence could be a milestone in understanding the molecular mechanisms of the pernicious traits and in developing effective weed control strategies to avoid yield loss in rice production.

RevDate: 2023-11-10
CmpDate: 2023-11-10

Pan R, Xiao M, Wu Z, et al (2023)

Associations of genetically predicted circulating levels of cytokines with telomere length: a Mendelian randomization study.

Frontiers in immunology, 14:1276257.

BACKGROUND: Telomere length (TL) has been regarded as a biomarker of aging, and TL shortening is associated with numerous chronic illnesses. The mounting evidence has shown that inflammatory cytokines are involved in maintaining or shortening TL, the causality of cytokines with TL remains unknown. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to estimate the underlying correlations of circulating inflammatory cytokines with TL.

METHODS: Genetic instrumental variables for inflammatory cytokines were identified through a genome-wide association study (GWAS) involving 8,293 European individuals. Summary statistics of TL were derived from a UK Bio-bank cohort comprising 472,174 samples of individuals with European descent. We employed the inverse-variance weighted (IVW) approach as our main analysis, and to ensure the reliability of our findings, we also conducted additional analyses including the weighted median, MR-Egger, MR pleiotropy residual sum and outlier test, and weighted model. Lastly, the reverse MR analyses were performed to estimate the likelihood of inverse causality between TL and the cytokines identified in the forward MR analysis. Cochran's Q test were employed to quantify the degree of heterogeneity.

RESULTS: After applying Bonferroni correction, a higher circulating level of Interleukin-7 (IL-7) was suggestively associated with TL maintaining (OR:1.01, 95%CI:1.00-1.02, P=0.032 by IVW method). The study also revealed suggestive evidence indicating the involvement of Interleukin-2 receptor, alpha subunit (IL-2Rα) level was negatively associated with TL maintaining (OR:0.98, 95%CI:0.96-1.00, P=0.045 by IVW method), and the weighted median approach was consistent (OR:0.99, 95%CI:0.97-1.00, P=0.035). According to the findings of reverse MR analysis, no significant causal relationship between TL and cytokines was explored. Our analysis did not reveal any substantial heterogeneity in the Single nucleotide polymorphisms or horizontal pleiotropy.

CONCLUSIONS: Our MR analysis yielded suggestive evidence supporting the causality between circulating IL-7 and IL-2Rα and telomere length, necessitating further investigations to elucidate the mechanisms by which these inflammatory cytokines may impact the progression of telomeres.

RevDate: 2023-11-10
CmpDate: 2023-11-10

Tang L, Li D, Ma Y, et al (2023)

The association between telomere length and non-alcoholic fatty liver disease: a prospective study.

BMC medicine, 21(1):427.

BACKGROUND: Research on the association between telomere length (TL) and incident non-alcoholic fatty liver disease (NAFLD) is limited. This study examined this association and further assessed how TL contributes to the association of NAFLD with its known risk factors.

METHODS: Quantitative PCR (polymerase chain reaction) was employed to assess leucocyte telomere length. Polygenic risk score (PRS) for NAFLD, air pollution score, and lifestyle index were constructed. Cox proportional hazard models were conducted to estimate the hazard ratios (HRs) and 95% confidence intervals.

RESULTS: Among 467,848 participants in UK Biobank, we identified 4809 NAFLD cases over a median follow-up of 12.83 years. We found that long TL was associated with decreased risk of incident NAFLD, as each interquartile range increase in TL resulted in an HR of 0.93 (95% CI 0.89, 0.96). TL partly mediated the association between age and NAFLD (proportion mediated: 15.52%). When assessing the joint effects of TL and other risk factors, the highest risk of NAFLD was found in participants with low TL and old age, low TL and high air pollution score, low TL and unfavorable lifestyle, and low TL and high PRS, compared to each reference group. A positive addictive interaction was observed between high PRS and low TL, accounting for 14.57% (2.51%, 27.14%) of the risk of NAFLD in participants with low telomere length and high genetic susceptibility.

CONCLUSIONS: Long telomere length was associated with decreased risk of NAFLD incidence. Telomere length played an important role in NAFLD.

RevDate: 2023-11-08

Kotecha EA, Zhang L, Aboklaish A, et al (2023)

Association of early and current life factors with telomere length in preterm-born children.

PloS one, 18(11):e0293589.

BACKGROUND: Telomeres shorten after each cell division. Since preterm-born babies are delivered early and often suffer from inflammatory conditions such as bronchopulmonary dysplasia (BPD), their telomere length may be altered.

OBJECTIVES: We assessed associations of early and current life factors with telomere length in saliva samples obtained from 7-12-year-old children born at ≤34 weeks' gestation and term-born controls.

STUDY DESIGN: Relative telomere length was measured by qPCR on extracted DNA. Groups were compared using independent t-tests or ANOVA with post-hoc correction. Linear regression analysis was also used.

RESULTS: 534 children had satisfactory telomere data including 383 who were preterm-born (mean (SD) birthweight 1732g (558g), gestation 31.1 (2.6) weeks) and 151 term-born (3464g (510g); 39.8 (1.3) weeks). Telomere length was longer in children who had intrauterine growth restriction (IUGR) at birth: mean (SD): 464.6 (166.3) vs. 418.6 (110.7) in the no-IUGR group; in females: 440.2 (130.1) vs. 405.7 (101.5) in males; and in the least deprived group (397.8 (95.0) vs. 437.6 (121.9) most vs least deprivation quintile). Differences were most notable in females with IUGR. However, telomere length was not different between the preterm and term groups; the BPD and no BPD groups nor was it related to lung function or cardiovascular measurements. In multivariable regression analyses, telomere length was associated with sex, IUGR and deprivation with the greatest difference observed in females with IUGR.

CONCLUSIONS: Telomere length was associated with sex, IUGR and deprivation, especially in females with IUGR, but not with prematurity, BPD, lung function or cardiovascular measurements.

RevDate: 2023-11-07

Sidali S, Borie R, de Fontbrune FS, et al (2023)

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

Hepatology (Baltimore, Md.) pii:01515467-990000000-00633 [Epub ahead of print].

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases.

APPROACH AND RESULTS: Retrospective multicentre analysis of liver disease (transaminases>30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n=1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease (PSVD) in 48%, and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and hepatocellular carcinoma occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group (80/396, (20%)), OR 12.9 (CI95% 7.8-21.3, p<0.001).

CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild they may be associated with severe disease. PSVD and cirrhosis were the most frequent lesions suggesting that the mechanism of action is multifactorial.

RevDate: 2023-11-06

Bountziouka V, Nelson CP, Codd V, et al (2023)

Dietary patterns and practices and leucocyte telomere length: Findings from the UK Biobank.

RevDate: 2023-11-06

Wang Y, Zhu W, Jang Y, et al (2023)

The RNA-binding motif protein 14 regulates telomere integrity at the interface of TERRA and telomeric R-loops.

Nucleic acids research pii:7335759 [Epub ahead of print].

Telomeric repeat-containing RNA (TERRA) and its formation of RNA:DNA hybrids (or TERRA R-loops), influence telomere maintenance, particularly in human cancer cells that use homologous recombination-mediated alternative lengthening of telomeres. Here, we report that the RNA-binding motif protein 14 (RBM14) is associated with telomeres in human cancer cells. RBM14 negatively regulates TERRA expression. It also binds to TERRA and inhibits it from forming TERRA R-loops at telomeres. RBM14 depletion has several effects, including elevated TERRA levels, telomeric R-loops, telomere dysfunction-induced DNA damage foci formation, particularly in the presence of DNA replication stress, pRPA32 accumulation at telomeres and telomere signal-free ends. Thus, RBM14 protects telomere integrity via modulating TERRA levels and its R-loop formation at telomeres.

RevDate: 2023-11-07

He S, Weng D, Zhang Y, et al (2023)

A telomere-to-telomere reference genome provides genetic insight into the pentacyclic triterpenoid biosynthesis in Chaenomeles speciosa.

Horticulture research, 10(10):uhad183.

Chaenomeles speciosa (2n = 34), a medicinal and edible plant in the Rosaceae, is commonly used in traditional Chinese medicine. To date, the lack of genomic sequence and genetic studies has impeded efforts to improve its medicinal value. Herein, we report the use of an integrative approach involving PacBio HiFi (third-generation) sequencing and Hi-C scaffolding to assemble a high-quality telomere-to-telomere genome of C. speciosa. The genome comprised 650.4 Mb with a contig N50 of 35.5 Mb. Of these, 632.3 Mb were anchored to 17 pseudo-chromosomes, in which 12, 4, and 1 pseudo-chromosomes were represented by a single contig, two contigs, and four contigs, respectively. Eleven pseudo-chromosomes had telomere repeats at both ends, and four had telomere repeats at a single end. Repetitive sequences accounted for 49.5% of the genome, while a total of 45 515 protein-coding genes have been annotated. The genome size of C. speciosa was relatively similar to that of Malus domestica. Expanded or contracted gene families were identified and investigated for their association with different plant metabolisms or biological processes. In particular, functional annotation characterized gene families that were associated with the biosynthetic pathway of oleanolic and ursolic acids, two abundant pentacyclic triterpenoids in the fruits of C. speciosa. Taken together, this telomere-to-telomere and chromosome-level genome of C. speciosa not only provides a valuable resource to enhance understanding of the biosynthesis of medicinal compounds in tissues, but also promotes understanding of the evolution of the Rosaceae.

RevDate: 2023-11-05

Zhao L, Jin W, Zhang T, et al (2023)

Association between the dietary antioxidant index and relative telomere length of leukocytes in the Chinese population.

The British journal of nutrition pii:S0007114523002544 [Epub ahead of print].

Dietary antioxidant indices (DAI) may be potentially associated with relative telomere length in leukocytes (RTL). This study aimed to investigate the relationship between DAI and RTL. A cross-sectional study involving 1656 participants was conducted. A generalized linear regression model (GLM) and a restricted cubic spline (RCS) model were used to assess the correlation of DAI and its components with RTL. Generalized linear regression analysis revealed that DAI (β = 0.005, P = 0.002) and the intake of its constituents vitamin C (β = 0.043, P = 0.027), vitamin E (β = 0.088, P < 0.001), selenium (β = 0.075, P = 0.003), and zinc (β = 0.075, P = 0.023) were significantly and positively correlated with RTL. Gender-stratified analysis showed that DAI (β = 0.006, P = 0.005) and its constituents vitamin E (β = 0.083, P = 0.012), selenium (β = 0.093, P = 0.006), and zinc (β = 0.092, P = 0.034) were significantly and positively correlated with RTL among females. Meanwhile, among males, only vitamin E intake (β = 0.089, P = 0.013) was significantly and positively associated with RTL. RCS analysis revealed linear positive associations between DAI and its constituents' (vitamin E, selenium, and zinc) intake and RTL in the total population. Sex-stratified analysis revealed a linear positive correlation between DAI and its constituents' (vitamin E, selenium, and zinc) intake and RTL in females. Our study found a significant positive correlation between DAI and RTL, with gender differences.

RevDate: 2023-11-05

Elbadry MI, Tawfeek A, Hirano T, et al (2023)

A rare homozygous variant in TERT gene causing variable bone marrow failure, fragility fractures, rib anomalies and extremely short telomere lengths with high serum IgE.

British journal of haematology [Epub ahead of print].

By whole exome sequencing, we identified a homozygous c.2086 C→T (p.R696C) TERT mutation in patients who present with a spectrum of variable bone marrow failure (BMF), raccoon eyes, dystrophic nails, rib anomalies, fragility fractures (FFs), high IgE level, extremely short telomere lengths (TLs), and skewed numbers of cytotoxic T cells with B and NK cytopenia. Haploinsufficiency in the other family members resulted in short TL and osteopenia. These patients also had the lowest bone mineral density Z-score compared to other BMF-patients. Danazol/zoledronic acid improved the outcomes of BMF and FFs. This causative TERT variant has been observed in one family afflicted with dyskeratosis congenita (DC), and thus, we also define a second report and new phenotype related to the variant which should be suspected in severe cases of DC with co-existent BMF, FFs, high IgE level and rib anomalies.

RevDate: 2023-11-03

Miga KH, EE Eichler (2023)

Envisioning a new era: Complete genetic information from routine, telomere-to-telomere genomes.

American journal of human genetics, 110(11):1832-1840.

Advances in long-read sequencing and assembly now mean that individual labs can generate phased genomes that are more accurate and more contiguous than the original human reference genome. With declining costs and increasing democratization of technology, we suggest that complete genome assemblies, where both parental haplotypes are phased telomere to telomere, will become standard in human genetics. Soon, even in clinical settings where rigorous sample-handling standards must be met, affected individuals could have reference-grade genomes fully sequenced and assembled in just a few hours given advances in technology, computational processing, and annotation. Complete genetic variant discovery will transform how we map, catalog, and associate variation with human disease and fundamentally change our understanding of the genetic diversity of all humans.

RevDate: 2023-11-06
CmpDate: 2023-11-06

Rosso I, Jones-Weinert C, Rossiello F, et al (2023)

Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs.

Nature communications, 14(1):7086.

Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism activated in ~10-15% of cancers, characterized by telomeric damage. Telomeric damage-induced long non-coding RNAs (dilncRNAs) are transcribed at dysfunctional telomeres and contribute to telomeric DNA damage response (DDR) activation and repair. Here we observed that telomeric dilncRNAs are preferentially elevated in ALT cells. Inhibition of C-rich (teloC) dilncRNAs with antisense oligonucleotides leads to DNA replication stress responses, increased genomic instability, and apoptosis induction selectively in ALT cells. Cell death is dependent on DNA replication and is increased by DNA replication stress. Mechanistically, teloC dilncRNA inhibition reduces RAD51 and 53BP1 recruitment to telomeres, boosts the engagement of BIR machinery, and increases C-circles and telomeric sister chromatid exchanges, without increasing telomeric non-S phase synthesis. These results indicate that teloC dilncRNA is necessary for a coordinated recruitment of DDR factors to ALT telomeres and it is essential for ALT cancer cells survival.

RevDate: 2023-11-04

Scorza FA, Finsterer J, Beltramim L, et al (2023)


RevDate: 2023-11-03

Tsatsakis A, Renieri E, Tsoukalas D, et al (2023)

A novel nutraceutical formulation increases telomere length and activates telomerase activity in middle‑aged rats.

Molecular medicine reports, 28(6):.

Telomeres are major contributors to cell fate and aging through their involvement in cell cycle arrest and senescence. The accelerated attrition of telomeres is associated with aging‑related diseases, and agents able to maintain telomere length (TL) through telomerase activation may serve as potential treatment strategies. The aim of the present study was to assess the potency of a novel telomerase activator on TL and telomerase activity in vivo. The administration of a nutraceutical formulation containing Centella asiatica extract, vitamin C, zinc and vitamin D3 in 18‑month‑old rats for a period of 3 months reduced the telomere shortening rate at the lower supplement dose and increased mean the TL at the higher dose, compared to pre‑treatment levels. TL was determined using the Q‑FISH method in peripheral blood mononuclear cells collected from the tail vein of the rats and cultured with RPMI‑1640 medium. In both cases, TLs were significantly longer compared to the untreated controls (P≤0.001). In addition, telomerase activity was increased in the peripheral blood mononuclear cells of both treatment groups. On the whole, the present study demonstrates that the nutraceutical formulation can maintain or even increase TL and telomerase activity in middle‑aged rats, indicating a potential role of this formula in the prevention and treatment of aging‑related diseases.

RevDate: 2023-11-05

Prasad A, Lin J, Jelliffe-Pawlowski L, et al (2023)

Sub-optimal maternal gestational gain is associated with shorter leukocyte telomere length at birth in a predominantly Latinx cohort of newborns.

Maternal health, neonatology and perinatology, 9(1):14.

OBJECTIVE: To assess in utero exposures associated with leukocyte telomere length (LTL) at birth and maternal LTL in a primarily Latinx birth cohort.

STUDY DESIGN: Mothers and newborns were recruited postnatally before 24 h of life. Newborn LTL was collected via heelstick at birth and maternal LTL was collected postnatally. LTL was determined by quantitative PCR. Using a longitudinal design, we evaluated associations between neonatal and maternal LTL and appropriate maternal gestational gain as indicated by the American College of Obstetrics and Gynecology (ACOG).

RESULT: Mean infant LTL was 2.02 ± 0.30 T/S (n = 386) and maternal LTL was 1.54 ± 0.26 T/S (n = 58). Independent risk factors for shorter LTL at birth included longer gestational duration (Coeff:-0.03, 95%CI: -0.05-0.01;p < 0.01) and maternal gestational weight gain below ACOG recommendations (Coeff:-0.10, 95%CI: -0.18 - -0.02; p = 0.01).

CONCLUSION: Gestational weight gain below ACOG recommendations may adversely impact neonatal health in Latinx infants as indicated by shorter LTL at birth.

RevDate: 2023-11-03

Liu J, Sha S, Wang J, et al (2023)

Development and Validation of a Prognosis-Prediction Signature for Patients with Lung Adenocarcinoma Based on 11 Telomere-Related Genes.

Frontiers in bioscience (Landmark edition), 28(10):254.

BACKGROUND: The occurrence and progression of lung cancer are correlated with telomeres and telomerase. Telomere length is reduced in the majority of tumors, including lung cancers. Telomere length variations have been associated with lung cancer risk and may serve as therapeutic targets as well as predictive biomarkers for lung cancer. Nevertheless, the effects of telomere-associated genes on lung cancer prognosis have not been thoroughly studied. We aim to investigate the relationship between telomere-associated genes and lung cancer prognosis.

METHODS: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used as training sets to build a predictive model. Three integrated Gene Expression Omnibus datasets served as validation sets. Using cluster consistency analysis and regression with the least absolute shrinkage and selection operator, we developed a telomere-related gene risk signature (TMGsig) based on 11 overall survival-related genes (RBBP8, PLK1, DSG2, HOXA7, ANAPC4, CSNK1E, SYAP1, ALDOA, PHF1, MUTYH, and PGS1).

RESULTS: The results indicated a negative outcome for the high-risk score group. Immunological microenvironment and somatic mutations differed between the high- and low-risk groups. A statistically significant difference existed between the low-risk and high-risk groups in terms of the expression levels of B cells and CD4 cells, and the risk score was essentially inversely linked with immune cell expression.

CONCLUSIONS: TMGsig can predict outcomes in patients with lung adenocarcinoma.

RevDate: 2023-11-02

Ulak M, Kvestad I, Chandyo RK, et al (2023)

The effect of vitamin B12 supplementation on leukocyte telomere length in mildly stunted Nepalese children: A secondary outcome of a randomized controlled trial.

The Journal of nutrition pii:S0022-3166(23)72669-2 [Epub ahead of print].

BACKGROUND: Vitamin B12 is essential for DNA synthesis and genome stability. A deficiency of vitamin B12 is associated with telomere shortening, genomic aging, and increased risk of chronic disease and mortality.

OBJECTIVES: The study aims to determine the effect of vitamin B12 supplementation on leukocyte telomere length in infants at risk of vitamin B12 deficiency.

METHODS: The study was a predefined secondary analysis of a randomized controlled trial enrolling 600 Nepalese infants aged 6 -11 months, who were supplemented with 2 μg (2-3 recommended daily allowances) vitamin B12 or placebo daily for one year. At the end of the study, Leukocyte telomere length (LTL) was measured in 497 participants. Mean LTL was compared between the treatment arms in the full sample and predefined subgroups based on markers of vitamin B12 status, hemoglobin, sex, and growth indices.

RESULTS: LTL at end-study did not differ between the vitamin B12 and placebo arm with a standardized mean difference (95% CI) of 0.04 (-0.14, 0.21). There was no effect of vitamin B12 on LTL in any of the subgroups.

CONCLUSIONS: Providing daily vitamin B12 for one year during infancy in a population at risk of vitamin B12 deficiency does not affect LTL.

CLINICAL TRIAL REGISTRATION: NCT02272842, registered October 21, 2014, Universal Trial Number: U1111-1161-5187 (September 8, 2014).

RevDate: 2023-11-02

Medoro A, Saso L, Scapagnini G, et al (2023)

NRF2 signaling pathway and telomere length in aging and age-related diseases.

Molecular and cellular biochemistry [Epub ahead of print].

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is well recognized as a critical regulator of redox, metabolic, and protein homeostasis, as well as the regulation of inflammation. An age-associated decline in NRF2 activity may allow oxidative stress to remain unmitigated and affect key features associated with the aging phenotype, including telomere shortening. Telomeres, the protective caps of eukaryotic chromosomes, are highly susceptible to oxidative DNA damage, which can accelerate telomere shortening and, consequently, lead to premature senescence and genomic instability. In this review, we explore how the dysregulation of NRF2, coupled with an increase in oxidative stress, might be a major determinant of telomere shortening and age-related diseases. We discuss the relevance of the connection between NRF2 deficiency in aging and telomere attrition, emphasizing the importance of studying this functional link to enhance our understanding of aging pathologies. Finally, we present a number of compounds that possess the ability to restore NRF2 function, maintain a proper redox balance, and preserve telomere length during aging.

RevDate: 2023-11-02

Chebly A, Khalil C, Kuzyk A, et al (2023)

T-cell lymphocytes' aging clock: telomeres, telomerase and aging.

Biogerontology [Epub ahead of print].

Aging is the decline of physiological capabilities required for life maintenance and reproduction over time. The human immune cells, including T-cells lymphocytes, undergo dramatic aging-related changes, including those related to telomeres and telomerase. It was demonstrated that telomeres and telomerase play crucial roles in T-cell differentiation, aging, and diseases, including a well-documented link between short telomeres and telomerase activation demonstrated in several T-cells malignancies. Herein, we provide a comprehensive review of the literature regarding T-cells' telomeres and telomerase in health and age related-diseases.

RevDate: 2023-11-02

Wei M, Huang Y, Mo C, et al (2023)

Telomere-to-telomere genome assembly of melon (Cucumis melo L. var. inodorus) provides a high-quality reference for meta-QTL analysis of important traits.

Horticulture research, 10(10):uhad189.

Melon is an important horticultural crop with extensive diversity in many horticultural groups. To explore its genomic diversity, it is necessary to assemble more high-quality complete genomes from different melon accessions. Meanwhile, a large number of QTLs have been mapped in several studies. Integration of the published QTLs onto a complete genome can provide more accurate information for candidate gene cloning. To address these problems, a telomere-to-telomere (T2T) genome of the elite melon landrace Kuizilikjiz (Cucumis melo L. var. inodorus) was de novo assembled and all the published QTLs were projected onto it in this study. The results showed that a high-quality Kuizilikjiz genome with the size of 379.2 Mb and N50 of 31.7 Mb was de novo assembled using the combination of short reads, PacBio high-fidelity long reads, Hi-C data, and a high-density genetic map. Each chromosome contained the centromere and telomeres at both ends. A large number of structural variations were observed between Kuizilikjiz and the other published genomes. A total of 1294 QTLs published in 67 studies were collected and projected onto the T2T genome. Several clustered, co-localized, and overlapped QTLs were determined. Furthermore, 20 stable meta-QTLs were identified, which significantly reduced the mapping intervals of the initial QTLs and greatly facilitated identification of the candidate genes. Collectively, the T2T genome assembly together with the numerous projected QTLs will not only broaden the high-quality genome resources but also provide valuable and abundant QTL information for cloning the genes controlling important traits in melon.

RevDate: 2023-11-01

Pirtea P, Keefe DL, Ayoubi JM, et al (2023)

Telomere length: a marker for reproductive aging?.

Fertility and sterility pii:S0015-0282(23)01949-0 [Epub ahead of print].

The improvements accomplished in ART have emphasized more than ever the role played by the chronological age notably, for predicting oocyte quality. Studies in cellular aging have directed research on telomere length measurements as possible marker of functional aging and notably, female reproductive outcome. While further research is still needed, encouraging results are already available on the possibility that leucocyte telomere length may be a useful parameter for assessing reproductive potential in aging women.

RevDate: 2023-11-01

Al Awadhi R, Alwehaidah MS, Al Roomy MS, et al (2023)

Relative Telomere length in cervical exfoliated cells among women with high- risk human papillomavirus.

Pathobiology : journal of immunopathology, molecular and cellular biology pii:000534917 [Epub ahead of print].

INTRODUCTION: This study investigates and compares the relative telomere length (RTL) outcome of high-risk (hr) human papillomavirus (HPV)-infected normal, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL) cervical samples to HPV-free normal cervical samples.

METHODS: This study used archived cervical samples and obtained cytology and histology data. HPV genotyping was conducted using Sanger sequencing and RTL was performed using real-time quantitative polymerase chain reaction.

RESULTS: This study investigated 287 cervical samples, including 100 normal and hr-HPV-negative samples from the control group, 44 normal and hr-HPV-infected samples, and 143 SIL and hr-HPV-infected samples. The RTL in hr-HPV-infected samples, including the SIL and normal sample groups, were significantly longer than that in the control group. RTL in HSIL (5.13 ± 3.22) and LSIL (2.86 ± 2.81) were significantly different (P < 0.001). The RTL of cervical intraepithelial neoplasia (CIN1) lesion (3.53 ± 2.53) differed significantly (P < 0.001) when compared to CIN2 and CIN3 lesions combined. The risk of developing cervical cancer was associated with RTL and was decreased with RTL.

CONCLUSION: This study revealed the strong potential of the RTL test in identifying women at risk of developing cervical cancer.

RevDate: 2023-10-30

Wang F, Chang L, Zhang X, et al (2023)

Effects of polycyclic aromatic hydrocarbon exposure and telomere length and their interaction on blood lipids in coal miners.

Journal of occupational and environmental medicine pii:00043764-990000000-00440 [Epub ahead of print].

OBJECTIVE: This study aimed to investigate the effects of PAH exposure and telomere length on lipids in coal miners.

METHODS: Basic personal information of 637 coal miners was collected by questionnaire survey. Logistic regression, the Bayesian kernel machine regression (BKMR) model, and weighted quantile sum (WQS) regression were used to analyze the effects of PAH metabolites and telomere length and their interactions on blood lipids.

RESULTS: High exposure to 9-hydroxyphenanthrene (OR = 1.586, 95% CI: 1.011-2.487) and telomere shortening (OR = 1.413, 95% CI: 1.005-1.985) were associated with dyslipidemia. WQS results showed that 9-hydroxyphenanthrene accounted for the largest proportion of dyslipidemia (weight = 0.66). The interaction results showed that high 9-hydroxyphenanthrene exposure and short telomeres were risk factors for dyslipidemia in coal miners (OR = 2.085, 95% CI: 1.121-3.879).

CONCLUSION: Our findings suggest that 9-hydroxyphenanthrene and shorter telomeres are risk factors for dyslipidemia, and their interaction increases the risk of dyslipidemia.

RevDate: 2023-10-31

Aghajanyan V, Bhupathy S, Sheikh S, et al (2023)

A Narrative Review of Telomere Length Modulation Through Diverse Yoga and Meditation Styles: Current Insights and Prospective Avenues.

Cureus, 15(9):e46130.

Mindfulness practices have demonstrated the potential to positively impact various aspects of human health associated with telomere length (TL) - a recognized marker of healthy aging and susceptibility to age-related diseases. This review seeks to conduct an in-depth comparative analysis, examining methodological variations, outcome assessments, strengths, weaknesses, and gaps across mindfulness-focused studies concerning TL and attrition rates. While emerging data tentatively suggest a positive connection between mindfulness practices and TL, a notable research gap pertains to establishing the clinically recommended dosage of yoga/meditation and mindfulness interventions to effectively influence TL. To address this gap, upcoming research should prioritize meticulous structuring, pedagogical precision, and vigilant monitoring of mindfulness interventions to yield psychological and physiological benefits across an appropriate timeframe and intensity. The amalgamation of yoga/meditation or mindfulness emerges as a promising avenue for enhancing the quality of life while counteracting the influence of telomere attrition in the spectrum of age-related diseases. The core objective of this review is to meticulously investigate the interplay between yoga/meditation and mindfulness practices and their potential impact on TL - an essential biomarker indicative of age-related health and well-being. To achieve this, our study methodically compares various methodological approaches, outcome measures, strengths, and limitations within relevant research endeavors focused on TL and attrition rates. Through this scrutiny, we highlight prevailing research gaps. Our analysis underscores the need for comprehensive research efforts aimed at establishing the optimal therapeutic regimen for yielding significant clinical effects on TL and overall health. In summation, our exploration emphasizes the urgency of further studies to unravel the most effective approaches for positively influencing TL and its implications for holistic health.

RevDate: 2023-10-30

Yu M, Yang D, Chen C, et al (2023)

Effects of SETD2 on telomere length and malignant transformation property of Met-5A after one-month crocidolite exposure.

Journal of environmental science and health. Part C, Toxicology and carcinogenesis [Epub ahead of print].

Crocidolite is a carcinogen contributing to the pathogenesis of malignant mesothelioma. This study aimed to characterize the possible telomere-related events mediating the malignant transformation of mesothelial cells with and without SETD2 under crocidolite exposure. The crocidolite concentration resulting in 90% viable SETD2 knockout Met-5A (Met-5A[SETD2-KO]) and Met-5A were estimated to be 0.71 μg/cm[2] and 1.8 μg/cm[2], respectively, during 72 h of exposure, which was further employed in chronical crocidolite exposure during a 72 h exposure interval per time up to 1 month. Chronical crocidolite-exposed Met-5A[SETD2-KO] (chronical Cro-Met-5A[SETD2-KO]) had higher colony formation and increased telomerase reverse transcriptase (TERT) protein levels than chronical crocidolite-exposed Met-5A (chronical Cro-Met-5A) and Met-5A[SETD2-KO]. Chronical Cro-Met-5A[SETD2-KO] had longer telomere length (TL) than chronical Cro-Met-5A, although there were no changes in TL for either chronical Cro-Met-5A or chronical Cro-Met-5A[SETD2-KO] compared with their corresponding cells without crocidolite exposure. BIBR 1532, an inhibitor targeting TERT, partially reduced colony formation and TL for chronical Cro-Met-5A[SETD2-KO], while BIBR 1532 reduced TL but had no effect on colony formation for chronical Cro-Met-5A. Therefore, SETD2 deficient mesothelial cells are susceptible to malignant transformation during chronical crocidolite exposure, and TERT-dependent TL modification likely partially drives SETD2 loss-mediated early onset of mesothelial malignant transformation.

RevDate: 2023-10-28

Luo H, Wang X, You C, et al (2023)

Telomere-to-telomere genome of the allotetraploid legume Sesbania cannabina reveals transposon-driven subgenome divergence and mechanisms of alkaline stress tolerance.

Science China. Life sciences [Epub ahead of print].

Alkaline soils pose an increasing problem for agriculture worldwide, but using stress-tolerant plants as green manure can improve marginal land. Here, we show that the legume Sesbania cannabina is very tolerant to alkaline conditions and, when used as a green manure, substantially improves alkaline soil. To understand genome evolution and the mechanisms of stress tolerance in this allotetraploid legume, we generated the first telomere-to-telomere genome assembly of S. cannabina spanning ∼2,087 Mb. The assembly included all centromeric regions, which contain centromeric satellite repeats, and complete chromosome ends with telomeric characteristics. Further genome analysis distinguished A and B subgenomes, which diverged approximately 7.9 million years ago. Comparative genomic analysis revealed that the chromosome homoeologs underwent large-scale inversion events (>10 Mb) and a significant, transposon-driven size expansion of the chromosome 5A homoeolog. We further identified four specific alkali-induced phosphate transporter genes in S. cannabina; these may function in alkali tolerance by relieving the deficiency in available phosphorus in alkaline soil. Our work highlights the significance of S. cannabina as a green tool to improve marginal lands and sheds light on subgenome evolution and adaptation to alkaline soils.

RevDate: 2023-10-30
CmpDate: 2023-10-30

Bräuer JA, Hammerl JA, El-Mustapha S, et al (2023)

The Novel Yersinia enterocolitica Telomere Phage vB_YenS_P840 Is Closely Related to PY54, but Reveals Some Striking Differences.

Viruses, 15(10):.

Telomere phages are a small group of temperate phages, whose prophages replicate as a linear plasmid with covalently closed ends. They have been isolated from some Enterobacteriaceae and from bacterial species living in aquatic environments. Phage PY54 was the first Yersinia (Y.) enterocolitica telomere phage isolated from a nonpathogenic O:5 strain, but recently a second telomeric Yersinia phage (vB_YenS_P840) was isolated from a tonsil of a wild boar in Germany. Both PY54 and vB_YenS_P840 (P840) have a siphoviridal morphology and a similar genome organization including the primary immunity region immB and telomere resolution site telRL. However, whereas PY54 only possesses one prophage repressor for the lysogenic cycle, vB_YenS_P840 encodes two. The telRL region of this phage was shown to be processed by the PY54 protelomerase under in vivo conditions, but unlike with PY54, a flanking inverted repeat was not required for processing. A further substantial difference between the phages is their host specificity. While PY54 infects Y. enterocolitica strains belonging to the serotypes O:5 and O:5,27, vB_YenS_P840 exclusively lyses O:3 strains. As the tail fiber and tail fiber assembly proteins of the phages differ significantly, we introduced the corresponding genes of vB_YenS_P840 by transposon mutagenesis into the PY54 genome and isolated several mutants that were able to infect both serotypes, O:5,27 and O:3.

RevDate: 2023-10-30
CmpDate: 2023-10-30

Ortega-Vázquez A, Sánchez-Badajos S, Ramírez-García MÁ, et al (2023)

Longitudinal Changes in Mitochondrial DNA Copy Number and Telomere Length in Patients with Parkinson's Disease.

Genes, 14(10):.

Parkinson's disease (PD) pathophysiology includes mitochondrial dysfunction, neuroinflammation, and aging as its biggest risk factors. Mitochondrial DNA copy number (mtDNA-CN) and telomere length (TL) are biological aging markers with inconclusive results regarding their association with PD. A case-control study was used to measure TL and mtDNA-CN using qPCR in PBMCs. PD patients were naive at baseline (T0) and followed-up at one (T1) and two (T2) years after the dopaminergic treatment (DRT). Plasmatic cytokines were determined by ELISA in all participants, along with clinical parameters of patients at T0. While TL was shorter in patients vs. controls at all time points evaluated (p < 0.01), mtDNA-CN showed no differences. An increase in mtDNA-CN and TL was observed in treated patients vs. naive ones (p < 0.001). Our statistical model analyzed both aging markers with covariates, showing a strong correlation between them (r = 0.57, p < 0.01), and IL-17A levels positively correlating with mtDNA-CN only in untreated patients (r = 0.45, p < 0.05). TL and mtDNA-CN could be useful markers for monitoring inflammation progression or treatment response in PD. DRT might modulate TL and mtDNA-CN, reflecting a compensatory mechanism to counteract mitochondrial dysfunction in PD, but this needs further investigation.

RevDate: 2023-10-30
CmpDate: 2023-10-30

Sato M, Wai KM, Itoh K, et al (2023)

Does the Protective Effect of Zinc on Telomere Length Depend on the Presence of Hypertension or Type 2 Diabetes? Results from the Iwaki Health Promotion Project, Japan.

Nutrients, 15(20):.

Telomeres, repeated TTAGGG sequences at chromosomal ends, shorten with age and indicate cellular lifespan. Zinc can protect against telomere damage through its anti-oxidative effect. Meanwhile, telomere shortening was correlated with metabolic diseases of hypertension and type 2 diabetes. The objective of this study was to investigate whether the association between zinc and telomere length differs by the presence or absence of hypertension/type 2 diabetes. This is a cross-sectional study with 1064 participants of the Iwaki area, Japan. Multiple linear regression models were performed to test the hypothesis. A higher serum zinc concentration was significantly associated with a longer G-tail length (β = 48.11, 95% confidence intervals [CI]: 25.69, 70.54, p < 0.001). By multivariate linear regression analysis, there was a significant positive association between zinc and G-tail length in both hypertensive (β = 46.84, 95%CI: 9.69, 84.0, p = 0.014) and non-hypertensive groups (β = 49.47, 95%CI: 20.75, 78.18, p = 0.001), while the association was significant only in the non-diabetes group (β = 50.82, 95%CI: 27.54, 74.11, p < 0.001). In conclusion, higher zinc concentration was significantly associated with longer G-tail length. The protective effect of zinc on G-tail did not differ by hypertension status; however, it disappeared in individuals with type 2 diabetes.

RevDate: 2023-10-28

Reljic D, Koller A, Herrmann HJ, et al (2023)

Differential Effects of Very-Low-Volume Exercise Modalities on Telomere Length, Inflammation, and Cardiometabolic Health in Obese Metabolic Syndrome Patients: A Subanalysis from Two Randomized Controlled Trials.

Antioxidants (Basel, Switzerland), 12(10):.

Oxidative stress (OS) and inflammation are features of metabolic syndrome (MetS) that can contribute to the shortening of telomere length (TL), a marker of cellular ageing. Research indicates that exercise can positively influence MetS-associated conditions and TL. However, the effects of low-volume exercise types on TL are still unknown. We investigated the impact of very-low-volume high-intensity interval training (LV-HIIT), one-set resistance training (1-RT), and whole-body electromyostimulation (WB-EMS) on TL, inflammation, and cardiometabolic indices in 167 MetS patients. Data were derived from two randomized controlled trials where patients were allocated to an exercise group (2 sessions/week, for 12 weeks) or a control group. All groups received standard-care nutritional weight loss counselling. TL was determined as the T/S ratio (telomere to single-copy gene amount). All groups significantly reduced body weight (p < 0.05), but the T/S-ratio (p < 0.001) only increased with LV-HIIT. OS-related inflammatory markers (C-reactive protein, interleukin-6, and lipopolysaccharide-binding protein) only decreased (p < 0.05) following LV-HIIT. The MetS severity z-score improved with LV-HIIT (p < 0.001) and 1-RT (p = 0.014) but not with WB-EMS. In conclusion, very-low-volume exercise modalities have differential effects on telomeres, inflammation, and cardiometabolic health. Only LV-HIIT but not strength-based low-volume exercise increased TL in MetS patients, presumably due to superior effects on OS-related inflammatory markers.

RevDate: 2023-10-27

Mori JO, Keegan J, Flynn RL, et al (2023)

Alternative lengthening of telomeres: mechanism and the pathogenesis of cancer.

Journal of clinical pathology pii:jcp-2023-209005 [Epub ahead of print].

Telomere maintenance and elongation allows cells to gain replicative immortality and evade cellular senescence during cancer development. While most cancers use telomerase to maintain telomere lengths, a subset of cancers engage the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT is present in 5%-10% of all cancers, although the prevalence is dramatically higher in certain cancer types, including complex karyotype sarcomas, isocitrate dehydrogenase-mutant astrocytoma (WHO grade II-IV), pancreatic neuroendocrine tumours, neuroblastoma and chromophobe hepatocellular carcinomas. ALT is maintained through a homology-directed DNA repair mechanism. Resembling break-induced replication, this aberrant process results in dramatic cell-to-cell telomere length heterogeneity, widespread chromosomal instability and chronic replication stress. Additionally, ALT-positive cancers frequently harbour inactivating mutations in either chromatin remodelling proteins (ATRX, DAXX and H3F3A) or DNA damage repair factors (SMARCAL1 and SLX4IP). ALT can readily be detected in tissue by assessing the presence of unique molecular characteristics, such as large ultrabright nuclear telomeric foci or partially single-stranded telomeric DNA circles (C-circles). Importantly, ALT has been validated as a robust diagnostic and prognostic biomarker for certain cancer types and may even be exploited as a therapeutic target via small molecular inhibitors and/or synthetic lethality approaches.

RevDate: 2023-10-27

Crocco P, De Rango F, Dato S, et al (2023)

The Shortening of Leukocyte Telomere Length Contributes to Alzheimer's Disease: Further Evidence from Late-Onset Familial and Sporadic Cases.

Biology, 12(10): pii:biology12101286.

Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are markers of premature cellular senescence. This may contribute to age-related diseases, including Alzheimer's disease (AD), and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case-control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, who were all from Calabria, a southern Italian region. Following regression analysis, telomeres were found significantly shorter in LOAD cases than in controls (48% and 41% decrease for sporadic and familial cases, respectively; p < 0.001 for both). Interestingly, LTL was associated with disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, and the presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the pathogenesis of LOAD.

RevDate: 2023-10-26

Serrano-León IM, Prieto P, M Aguilar (2023)

Telomere and subtelomere high polymorphism might contribute to the specificity of homologous recognition and pairing during meiosis in barley in the context of breeding.

BMC genomics, 24(1):642.

Barley (Hordeum vulgare) is one of the most popular cereal crops globally. Although it is a diploid species, (2n = 2x = 14) the study of its genome organization is necessary in the framework of plant breeding since barley is often used in crosses with other cereals like wheat to provide them with advantageous characters. We already have an extensive knowledge on different stages of the meiosis, the cell division to generate the gametes in species with sexual reproduction, such as the formation of the synaptonemal complex, recombination, and chromosome segregation. But meiosis really starts with the identification of homologous chromosomes and pairing initiation, and it is still unclear how chromosomes exactly choose a partner to appropriately pair for additional recombination and segregation. In this work we present an exhaustive molecular analysis of both telomeres and subtelomeres of barley chromosome arms 2H-L, 3H-L and 5H-L. As expected, the analysis of multiple features, including transposable elements, repeats, GC content, predicted CpG islands, recombination hotspots, G4 quadruplexes, genes and targeted sequence motifs for key DNA-binding proteins, revealed a high degree of variability both in telomeres and subtelomeres. The molecular basis for the specificity of homologous recognition and pairing occurring in the early chromosomal interactions at the start of meiosis in barley may be provided by these polymorphisms. A more relevant role of telomeres and most distal part of subtelomeres is suggested.

RevDate: 2023-10-26

PLOS ONE Editors (2023)

Retraction: Zinc sulfate contributes to promote telomere length extension via increasing telomerase gene expression, telomerase activity and change in the TERT gene promoter CpG island methylation status of human adipose-derived mesenchymal stem cells.

PloS one, 18(10):e0292985 pii:PONE-D-23-32290.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

SUPPORT ESP: Click covers to order from Amazon
The ESP project will earn a commission.

Good Beginner's Books

Although multicellular eukaryotes (MCEs) are the most visible component of the biosphere, they represent a highly derived and constrained evolutionary subset of the biosphere, unrepresentative of the vast, mostly unseen, microbial world of prokaryotic life that comprises at least half of the planet's biomass and most of its genetic diversity. The existence of telomeres is one component of the specialized biology of eukaryotes. R. Robbins

Electronic Scholarly Publishing
961 Red Tail Lane
Bellingham, WA 98226

E-mail: RJR8222 @

Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).


ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.


Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )