Length Of Telomere Repeats Research Articles

The State of the LPO-AOD System and the Relative Length of Telomeric Repeats in the Chromosomes of Blood Leukocytes in Obstructive Sleep Apnea Syndrome.

We analyzed the relative length of telomeric repeats in peripheral blood leukocytes and indicators of oxidative stress in 32 men (mean age 51.2±3.1 years) with obstructive sleep apnea syndrome (OSAS). The control group consisted of volunteers without OSAS. The relative length of telomeres was determined in a DNA sample isolated from venous whole blood samples. The length of telomeric repeats of chromosomes was determined using quantitative real-time PCR (3 times for each DNA sample); albumin served as an internal control. The intensity of LPO processes and antioxidant protection was assessed by conventional spectrophotometric methods. It was found that in patients with OSAS, the relative length of telomeric repeats was lower by 48%, the levels of substrates and products of LPO were higher (double bonds and diene conjugates by 34 and 19%, respectively), and antioxidant protection indicators were lower (concentrations of fat-soluble vitamins α-tocopherol and retinol by 18 and 19.3%, respectively, total antioxidant activity by 32.9%) than in volunteers of the control group. Thus, we can conclude that the nucleotide sequences are reduced in patients with OSAS under conditions of intensified free radical oxidation.

Association of variants of the relative length of telomeric repeats with coronary heart disease with old myocardial infarction

Association of variants of the relative length of telomeric repeats with coronary heart disease with old myocardial infarction

Genetic, parental and lifestyle factors influence telomere length

The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.

Telomeres, aging, and cancer: the big picture

AbstractThe role of telomeres in human health and disease is yet to be fully understood. The limitations of mouse models for the study of human telomere biology and difficulties in accurately measuring the length of telomere repeats in chromosomes and cells have diverted attention from many important and relevant observations. The goal of this perspective is to summarize some of these observations and to discuss the antagonistic role of telomere loss in aging and cancer in the context of developmental biology, cell turnover, and evolution. It is proposed that both damage to DNA and replicative loss of telomeric DNA contribute to aging in humans, with the differences in leukocyte telomere length between humans being linked to the risk of developing specific diseases. These ideas are captured in the Telomere Erosion in Disposable Soma theory of aging proposed herein.

A Prospective Study of Leukocyte Telomere Length and Risk of Gestational Diabetes in a Multiracial Cohort.

Short telomere length (TL), an indicator of cellular aging and oxidative stress, has been implicated in glucose homeostasis. Additionally, studies have illustrated that the association of TL with health outcomes may vary by age. Yet, data on the association between TL and gestational diabetes mellitus (GDM) are sparse and the potential effect modification by age remains unknown. We prospectively investigated TL in early pregnancy in relation to the subsequent GDM risk in a case-control study of 93 women with GDM and 186 randomly selected controls matched on age, race/ethnicity, and gestational weeks at blood collection. TL was measured using blood samples collected at 10-14 gestational weeks and reported as the T/S ratio, a ratio of telomere repeat length T to copy number of a single copy gene S. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression adjusted for major risk factors. Overall, TL was not significantly associated with GDM risk. The TL-GDM association was significantly modified by age (Pinteraction = 0.02). Shorter TL in early pregnancy was associated with an increased GDM risk among women <30 years old (adjusted OR comparing the shortest vs. longest tertile: 3.1, 95% CI = 1.2, 8.1), but not associated with GDM risk among women ≥30 years. Our findings suggest that TL in early pregnancy may be implicated in GDM development, particularly among younger women.

TelNet - a database for human and yeast genes involved in telomere maintenance

BackgroundThe ends of linear chromosomes, the telomeres, comprise repetitive DNA sequences in complex with proteins that protects them from being processed by the DNA repair machinery. Cancer cells need to counteract the shortening of telomere repeats during replication for their unlimited proliferation by reactivating the reverse transcriptase telomerase or by using the alternative lengthening of telomeres (ALT) pathway. The different telomere maintenance (TM) mechanisms appear to involve hundreds of proteins but their telomere repeat length related activities are only partly understood. Currently, a database that integrates information on TM relevant genes is missing.DescriptionTo provide a resource for studies that dissect TM features, we here introduce the TelNet database at http://www.cancertelsys.org/telnet/. It offers a comprehensive compilation of more than 2000 human and 1100 yeast genes linked to telomere maintenance. These genes were annotated in terms of TM mechanism, associated specific functions and orthologous genes, a TM significance score and information from peer-reviewed literature. This TM information can be retrieved via different search and view modes and evaluated for a set of genes as demonstrated for an exemplary application.ConclusionTelNet supports the annotation of genes identified from bioinformatics analysis pipelines to reveal possible connections with TM networks. We anticipate that TelNet will be a helpful resource for researchers that study telomeres.

Rif1 acts through Protein Phosphatase 1 but independent of replication timing to suppress telomere extension in budding yeast

The Rif1 protein negatively regulates telomeric TG repeat length in the budding yeast Saccharomyces cerevisiae, but how it prevents telomere over-extension is unknown. Rif1 was recently shown to control DNA replication by acting as a Protein Phosphatase 1 (PP1)-targeting subunit. Therefore, we investigated whether Rif1 controls telomere length by targeting PP1 activity. We find that a Rif1 mutant defective for PP1 interaction causes a long-telomere phenotype, similar to that of rif1Δ cells. Tethering PP1 at a specific telomere partially substitutes for Rif1 in limiting TG repeat length, confirming the importance of PP1 in telomere length control. Ablating Rif1–PP1 interaction is known to cause precocious activation of telomere-proximal replication origins and aberrantly early telomere replication. However, we find that Rif1 still limits telomere length even if late replication is forced through deletion of nearby replication origins, indicating that Rif1 can control telomere length independent of replication timing. Moreover we find that, even at a de novo telomere created after DNA synthesis during a mitotic block, Rif1–PP1 interaction is required to suppress telomere lengthening and prevent inappropriate recruitment of Tel1 kinase. Overall, our results show that Rif1 controls telomere length by recruiting PP1 to directly suppress telomerase-mediated TG repeat lengthening.

Telomeric repeat-containing RNA (TERRA) related to polycystic ovary syndrome (PCOS).

Telomeric repeat-containing RNA (TERRA) participates in the regulation of telomere length, and leucocyte telomere length (LTL) plays an important role in the pathophysiology of polycystic ovary syndrome (PCOS), but little is known about the role of TERRA in PCOS. To evaluate the role of TERRA and peripheral blood LTL in PCOS. Forty women with PCOS and 35 healthy women without PCOS were recruited. A prospective case-control study was performed. RNA fluorescence in situ hybridization (FISH) was used to detect TERRA expression in peripheral blood leucocyte. Quantitative PCR was used to measure TERRA expression and the mean LTL in the PCOS and control groups. We analysed the association between related clinical parameters and the age-adjusted ratio of the telomere repeat length (T/S ratio) or TERRA. Telomeric repeat-containing RNA was expressed in human peripheral blood leucocytes, and the signal was abolished after culture with RNase A. The age-adjusted LTLs were significantly longer in the PCOS group than in the control group (P < 0·01). The age-adjusted TERRA level was significantly lower in the PCOS group than in the control group (P < 0·01). Testosterone (TTE) was related positively to LTL and negatively to TERRA in the PCOS group (r = 0·532, P = 0·002; r = -0·477, P = 0·017). We found TERRA expression in human peripheral blood leucocytes, and LTLs were positively associated with PCOS. TERRA and testosterone play an important role in the LTL regulation in PCOS.

Ruxolitinib therapy and telomere length in myelofibrosis

Telomeres are specialized structures of repetitive nucleotide sequences that cap the ends of human chromosomes. Their main purpose is to maintain genome stability and integrity, and to protect the cell from progressive DNA shortening during repeated division. Human enzyme telomerase complex maintains the length of telomere repeats.1 Despite the high levels of telomerase activity in cancer cells, telomere shortening can still occur. Some recent reports describe reduced telomere length in myelofibrosis (MF) regardless of hydroxycarbamide therapy, suggesting a possible prognostic relevance for this biomarker.2, 3, 4 As yet, no studies have investigated telomere dynamics following treatment with ruxolitinib, a JAK1/2 inhibitor approved for the treatment of intermediate-2 and high risk MF, primary or post-polycythemia vera (PV) and essential thrombocytemia (ET).5

Histone modifications rather than the novel regional centromeres of Zymoseptoria tritici distinguish core and accessory chromosomes.

BackgroundSupernumerary chromosomes have been found in many organisms. In fungi, these “accessory” or “dispensable” chromosomes are present at different frequencies in populations and are usually characterized by higher repetitive DNA content and lower gene density when compared to the core chromosomes. In the reference strain of the wheat pathogen, Zymoseptoria tritici, eight discrete accessory chromosomes have been found. So far, no functional role has been assigned to these chromosomes; however, they have existed as separate entities in the karyotypes of Zymoseptoria species over evolutionary time. In this study, we addressed what—if anything—distinguishes the chromatin of accessory chromosomes from core chromosomes. We used chromatin immunoprecipitation combined with high-throughput sequencing (“ChIP-seq”) of DNA associated with the centromere-specific histone H3, CENP-A (CenH3), to identify centromeric DNA, and ChIP-seq with antibodies against dimethylated H3K4, trimethylated H3K9 and trimethylated H3K27 to determine the relative distribution and proportion of euchromatin, obligate and facultative heterochromatin, respectively.ResultsCentromeres of the eight accessory chromosomes have the same sequence composition and structure as centromeres of the 13 core chromosomes and they are of similar length. Unlike those of most other fungi, Z. tritici centromeres are not composed entirely of repetitive DNA; some centromeres contain only unique DNA sequences, and bona fide expressed genes are located in regions enriched with CenH3. By fluorescence microscopy, we showed that centromeres of Z. tritici do not cluster into a single chromocenter during interphase. We found dramatically higher enrichment of H3K9me3 and H3K27me3 on the accessory chromosomes, consistent with the twofold higher proportion of repetitive DNA and poorly transcribed genes. In contrast, no single histone modification tested here correlated with the distribution of centromeric nucleosomes.ConclusionsAll centromeres are similar in length and composed of a mixture of unique and repeat DNA, and most contain actively transcribed genes. Centromeres, subtelomeric regions or telomere repeat length cannot account for the differences in transfer fidelity between core and accessory chromosomes, but accessory chromosomes are greatly enriched in nucleosomes with H3K27 trimethylation. Genes on accessory chromosomes appear to be silenced by trimethylation of H3K9 and H3K27.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0033-5) contains supplementary material, which is available to authorized users.

Key Role of Promoter Methylation and Inactivation of MCPH1 Gene in Brain Tumors

Background: Microcephalin (MCPH1/BIRT1) is a putative tumor suppressor gene which has recently seized great attentions in cancer studies. The present study was conducted to seek the impact of MCPH1 promoter methylation on development of brain tumors and telomere repeat length (TRL). Methods: The brain tissue section provided from brain tumor patients and two normal brain autopsies were undergone DNA isolation. DNA samples treated with bisulfite sodium using DNA modification kit (Qiagen) were amplified in methylation specific polymerization chain reaction (MSP-PCR) confirmed by sequencing. Protein expression analysis was performed by immunofluorescence (IF) assay using antibodies against MCPH1, cyclin E and CDC25A proteins. The TRL of brain tumor patients was determined through quantitative fluorescent in situ hybridization (Q-FISH). Results: The MCPH1 gene promoter was methylated in 96.6% of the patients consistent with protein expression pattern and the telomere statue was confirmed by low or absence of signal in tumor cells. Conclusion: MCPH1 promoter methylation had strong association with TRL, tumor’s grade and stage (P < 0.05). TRL was meaningfully associated with grade and subtype pathology of brain tumors (P = 0.01). Further studies are required to clarify the exact role of MCPH1 gene on TRL and tumor suppression especially in brain tumors. J Neurol Res. 2014;4(5-6):133-138 doi: http://dx.doi.org/10.14740/jnr295e

Key Role of Promoter Methylation and Inactivation of MCPH1 Gene in Brain Tumors

Background: Microcephalin (MCPH1/BIRT1) is a putative tumor suppressor gene which has recently seized great attentions in cancer studies. The present study was conducted to seek the impact of MCPH1 promoter methylation on development of brain tumors and telomere repeat length (TRL). Methods: The brain tissue section provided from brain tumor patients and two normal brain autopsies were undergone DNA isolation. DNA samples treated with bisulfite sodium using DNA modification kit (Qiagen) were amplified in methylation specific polymerization chain reaction (MSP-PCR) confirmed by sequencing. Protein expression analysis was performed by immunofluorescence (IF) assay using antibodies against MCPH1, cyclin E and CDC25A proteins. The TRL of brain tumor patients was determined through quantitative fluorescent in situ hybridization (Q-FISH). Results: The MCPH1 gene promoter was methylated in 96.6% of the patients consistent with protein expression pattern and the telomere statue was confirmed by low or absence of signal in tumor cells. Conclusion: MCPH1 promoter methylation had strong association with TRL, tumor’s grade and stage (P &lt; 0.05). TRL was meaningfully associated with grade and subtype pathology of brain tumors (P = 0.01). Further studies are required to clarify the exact role of MCPH1 gene on TRL and tumor suppression especially in brain tumors. J Neurol Res. 2014;4(5-6):133-138 doi: http://dx.doi.org/10.14740/jnr295e

Direct human DNA damage by unfavorable environmental and climatic factors

To study the impact of simulated climatic conditions of the 2010 summer in Moscow on the telomere repeats of chromosomes in human blood cells. The climatic conditions of July-August 2010 in Moscow were simulated at the Medical Technical Complex, Institute of Biomedical Problems, Russian Academy of Sciences. The relative length of the telomeric repeats of blood cell chromosomes from 6 apparently healthy volunteers was measured by quantitative real-time polymerase chain reaction. These conditions were ascertained to lead to a statistically significant decline in the length of telomere repeats in the terminal portions of chromosomes by 15%. Environmental changes and abnormal temperature rises may result in oxidative stress accompanied by telomere shortening, which can be, in turn, a factor of premature aging.

A Possible New Mechanism in the Pathophysiology of Polycystic Ovary Syndrome (PCOS): The Discovery That Leukocyte Telomere Length Is Strongly Associated With PCOS

Telomeres are specialized chromatin structures located at the ends of eukaryotic chromosomes, and telomere length plays a clear role in various diseases. However, it is not known whether telomere length is related to polycystic ovary syndrome (PCOS). We hypothesized that leukocyte telomere length (LTL) plays an important role in the pathophysiology of PCOS. We used an established and validated quantitative PCR technique to measure the mean LTL in a large sample of PCOS patients and controls. We used logistic regression and multiple linear regression to analyze the association of PCOS and several related clinical parameters with the age-adjusted ratio of the telomere repeat length to the copy number of a single-copy gene (T/S). Individuals with PCOS (n = 698) exhibited significantly shorter LTLs than the controls (n = 611) after adjusting for age (0.764 ± 0.016 vs 0.876 ± 0.023; P = .001; odds ratio = 1.403; 95% confidence interval, 1.150-1.712). The mean telomere length in the leukocytes of PCOS patients was comparable to that of control individuals who were on average 6.16 years older. Individuals having shorter telomere lengths (middle and lowest tertile) had significantly higher disease risk than those having the longest telomere length (highest tertile) (odds ratio = 1.614; 95% confidence interval, 1.262-2.066; P = .0001) after adjusting for age. In addition, a significant correlation between the LTL and the level of dehydroepiandrosterone sulfate was observed in controls (r = -0.185; P = .01). We provide the first report that LTL is strongly associated with PCOS. This study suggests a new role for LTL in the pathophysiology of PCOS and might have important implications for our understanding of the etiology of the disease.

Silver birch telomeres shorten in tissue culture

Shortening of telomeres has been connected with ageing and loss of cell replication or regeneration capacity. The aim of the present study was to examine potential variation in the length of telomeric repeats in silver birch (Betula pendula Roth) using clonal materials consisting of different-aged outdoor trees and tissue cultures of seven genotypes. The overall average length of telomeres was 13.6 kb (±0.3), the minimum length of repeats in the different genotypes varied from 5.9 kb (±0.5) to 9.6 kb (±0.6), and the maximum length varied from 15.3 kb (±1.1) to 22.8 kb (±0.4). When germinated seeds and leaf and cambium samples from 15- and 80-year-old trees were compared, no correlation of ageing and the length of telomeric repeats was found. Positional variation in the telomere length was, however, observed in the cambium of mature trees, the stem base having longer repeats than the upper parts of the tree. Tissue cultures were found to have shorter telomeres than outdoor trees: prolonged culture, callus culture and stressful conditions were all observed to shorten telomeric repeats and should thus be avoided in birch micropropagation. There were significant differences among the studied silver birch genotypes in their telomere length, and these differences were consistent over the sample types. This is the first report on variation of telomeric repeats in a long-living organism studied with clonal materials.

Association of Shorter Leukocyte Telomere Repeat Length With Dementia and Mortality

Shortening of chromosomal telomeres is a consequence of cell division and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging. To determine whether shorter telomere length (TL), as measured in human blood samples, is associated with the development of Alzheimer disease and mortality. We studied available stored leukocyte DNA from a community-based study of aging using realtime polymerase chain reaction analysis to determine mean TL in our modification of a method measuring the ratio of telomere sequence to single-copy gene sequence. A multiethnic community-based study of aging and dementia. One thousand nine hundred eighty-three subjects 65 years or older. Mean (SD) age at blood draw was 78.3 (6.9) years; at death, 86.0 (7.4) years. Median follow-up for mortality was 9.3 years; 190 (9.6%) developed incident dementia. The TL was inversely related to age and shorter in men than women. Persons dying during follow-up had a shorter TL compared with survivors (mean [SD], 6218 [819] vs 6491 [881] base pairs [bp] [P.001]), even after adjustment for age, sex, education, and apolipoprotein E genotype. Individuals who developed dementia had significantly shorter TL (mean [SD], 6131 [798] bp for prevalent cases and 6315 [817] bp for incident cases) compared with those remaining dementia-free (6431 [864] bp). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (P=.05), but stratified analyses for sex showed that this association of age at onset of dementia with shorter TL was significant in women only. Our findings suggest that shortened leukocyte TL is associated with risks for dementia and mortality and may therefore be a marker of biological aging.

The Tale of the Telomeres Gets Ever-More Complex

The Tale of the Telomeres Gets Ever-More Complex

Epigenetic differences between sister chromatids?

Semi-conservative replication ensures that the DNA sequence of sister chromatids is identical except for replication errors and variation in the length of telomere repeats resulting from replicative losses and variable end processing. What happens with the various epigenetic marks during DNA replication is less clear. Many chromatin marks are likely to be copied onto both sister chromatids in conjunction with DNA replication, whereas others could be distributed randomly between sister chromatids. Epigenetic differences between sister chromatids could also emerge in a more predictable manner, for example, following processes that are associated with lagging strand DNA replication. The resulting epigenetic differences between sister chromatids could result in different gene expression patterns in daughter cells. This possibility has been difficult to test because techniques to distinguish between parental sister chromatids require analysis of single cells and are not obvious. Here, we briefly review the topic of sister chromatid epigenetics and discuss how the identification of sister chromatids in cells could change the way we think about asymmetric cell divisions and stochastic variation in gene expression between cells in general and paired daughter cells in particular.

Biological ageing is a key determinant in systemic sclerosis

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune cell activation and fibrosis of the skin and internal organs, occurring mainly in females. Although a lot of progress has been made in the discovery of genetic risk factors for SSc, environmental factors triggering onset of SSc have not been identified. This provides a foundation for the involvement of processes related to biological ageing to trigger SSc onset and perpetuation in the genetically susceptible host. Consequently, we have investigated key determinants of biological ageing, namely telomere attrition and the role of telosome proteins in the pathology of systemic sclerosis and how it impacts on individual leukocyte cell subsets. Epigenetic processes, such as telomere attrition have been implicated in SSc [1]. The length of telomeric DNA repeats shortens during replicative ageing of peripheral blood lymphocytes. This process is exacerbated by psychological, sociological and biological determinants [2,3]. As a consequence, telomere length reflects the “miles on the clock” of a given cell type. Proteinaceous components of the associatedtelosome arecomplicit in the sensing, signaling and repair of DNA damage [3]. These have a critical role inprotectingthe cell from excessive DNA damage, by facilitating cellular senescence and apoptosis. This study aimed to evaluate telosome biologyin an independent, clinically well-defined SSc cohorts. Moreover, we aimed to investigate whether there are differences in telomere attrition between different immune cell subsets and if these differences are accompanied by changes in expression of genes involved in telomere functioning.

Variation in telomeric repeats of Scots pine (Pinus sylvestris L.)

The shortening of telomeres, the specific structures at the end of the eukaryotic chromosomes, has been associated with ageing and loss of cell replication or regeneration capacity. The aim of this study was to determine the variation in telomeric repeats during the life-span of Scots pine (Pinus sylvestris L.) by studying different tissues and age groups ranging from immature embryos to cambium, buds, and needles of mature, 200-year-old trees. The telomeric repeats in Scots pine including interstitial and centromeric repeats ranged from 0.9 up to 25 kb, and true telomeres were evaluated to have a mean length of 19.3 kb (±SE 0.17). Telomeres were observed to shorten with increasing tissue differentiation, embryonal samples having the longest repeats with an average length of 21.1 (±0.34) to 21.7 kb (±0.42) and the needles having, on average, the shortest repeats of 18.1 kb (±0.24). After germination, ageing per se had no significant effect on the length of telomeric repeats in cambium, bud, or needle tissues. In the older trees (50–200 years of age), the telomeres in stem cambium showed shortening towards the tree top. This is the first observation on such a position-related variation in telomeric repeats. Finally, there was a remarkable genotypic variation in the length of telomeric repeats, and this was consistent over the tissue types. In the small number of tested donor trees, the genotypic differences were not related to regeneration ability in tissue culture.