Understanding the role of telomere attrition and epigenetic signatures in COVID-19 severity

Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres. The critical role of telomeres in cell proliferation and aging is illustrated in patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Here, the role of telomeres and telomerase in human biology is reviewed from a personal historical perspective.

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Nijmegen Breakage Syndrome (NBS) is a Telomeropathy: Analysis of Telomere Length in NBS Homo- and Heterozygotes and Humanized Nbs Mice

10.1101/571026 ◽

2019 ◽

Author(s):

Raneem Habib ◽

Ryong Kim ◽

Heidemarie Neitzel ◽

Ilja Demuth ◽

Krystyna Chrzanowska ◽

...

Keyword(s):

Telomere Length ◽

Cancer Incidence ◽

Genetic Instability ◽

Nijmegen Breakage Syndrome ◽

Survival Times ◽

Telomere Shortening ◽

Cancer Rate ◽

Telomere Attrition ◽

After Cancer

AbstractThe autosomal recessive genetic disorder Nijmegen breakage syndrome (NBS) is characterized by a defect in DNA double-strand break repair protein nibrin and chromosome instability associated with a high predisposition to cancer. Here we hypothesized that impaired nibrin/MRE11/RAD50 telomere maintenance complex may also affect telomere length and modulate the cancer phenotype.Telomere length was studied in blood from 38 homozygous and 27 heterozygous individuals, in one homozygous fetus, and in sex NBS lymphoblastoid cell lines (all with the founder mutation c.657_661del5), and in three humanized Nbs mice, using qPCR, TRF and Q-FISH.Telomere lengths were markedly but uniformly reduced to 20-40% of healthy controls. There was no correlation between telomere length and severity of clinical phenotype or age of death. By contrast, individual patients with very short telomeres displayed long survival times after cancer manifestation. Mildly accelerated telomere attrition was found in older NBS heterozygotes. In the NBS-fetus, the spinal cord, brain and heart had the longest telomeres, skin the shortest. Humanized Nbs mice (with much longer telo-meres than those in human beings) did not show accelerated telomere attrition.Our data clearly show that NBS is a secondary telomeropathy with unique features. Te- lomere attrition in NBS may cause genetic instability and contribute to the high cancer incidence in NBS. On the other hand, short telomeres may prevent an even worse pheno-type when a tumor has developed. These data may help to understand the high cancer rate in NBS and also the bifunctional role of telomere shortening in cancerogenesis.Author SummaryDNA damage is harmful because it leads to mutations in genes that initiate or accelerate cancerogenesis. The devastating consequences of DNA damage are manifested in diseases with non-functional repair pathways such as Nijmegen breakage syndrome (NBS). A common feature of these diseases is a high tumor incidence. However, cancer incidence varies and is not clear why it is highest for NBS. In a previous study, we have shown that the underlying nebrin mutation not only leads to defective DNA repair but also to higher degree of oxidative stress that generates further DNA lesions. Nibrin may play also an important role in protecting chromosome ends, the telomeres, from inap-propriate DNA repair. Therefore we examined the telomere length in NBS and show markedly reduced values in affected patients but not in NBC mice (with much milder phenotype and longer telomeres). Telomere attrition contributes to genetic instability and may thus contribute to the high cancer incidence in NBS. Individual patients with very short telomeres, however, displayed long survival times after cancer manifestation. Thus, short telomeres may also prevent an even worse phenotype when a tumor has developed. These data are fundamental to understanding the high cancer rate in NBS and also the bifunctional role of telomere shortening in cancer.

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Telomeres and Longevity: A Cause or an Effect?

International Journal of Molecular Sciences ◽

10.3390/ijms20133233 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3233 ◽

Cited By ~ 7

Author(s):

Huda Adwan Shekhidem ◽

Lital Sharvit ◽

Eva Leman ◽

Irena Manov ◽

Asael Roichman ◽

...

Keyword(s):

Telomere Length ◽

Ongoing Debate ◽

Telomere Attrition ◽

Age Related ◽

Mole Rat ◽

Naked Mole Rat ◽

Extreme Longevity ◽

Linear Chromosomes ◽

Biological State

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a “biological thermometer” that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

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The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective

International Journal of Molecular Sciences ◽

10.3390/ijms21030980 ◽

2020 ◽

Vol 21 (3) ◽

pp. 980 ◽

Cited By ~ 9

Author(s):

Yi-Chou Hou ◽

Chien-Lin Lu ◽

Tzu-Hang Yuan ◽

Min-Tser Liao ◽

Chia-Ter Chao ◽

...

Keyword(s):

Dna Methylation ◽

Histone Modification ◽

Vascular Calcification ◽

Calcium Deposition ◽

Non Coding Rna ◽

Physico Chemical ◽

Variable Combination ◽

Epigenetic Signatures ◽

Epigenetic Processes

Vascular calcification (VC) is an important complication among patients of advanced age, those with chronic kidney disease, and those with diabetes mellitus. The pathophysiology of VC encompasses passive occurrence of physico-chemical calcium deposition, active cellular secretion of osteoid matrix upon exposure to metabolically noxious stimuli, or a variable combination of both processes. Epigenetic alterations have been shown to participate in this complex environment, through mechanisms including DNA methylation, non-coding RNAs, histone modifications, and chromatin changes. Despite such importance, existing reviews fail to provide a comprehensive view of all relevant reports addressing epigenetic processes in VC, and cross-talk between different epigenetic machineries is rarely examined. We conducted a systematic review based on PUBMED and MEDLINE databases up to 30 September 2019, to identify clinical, translational, and experimental reports addressing epigenetic processes in VC; we retrieved 66 original studies, among which 60.6% looked into the pathogenic role of non-coding RNA, followed by DNA methylation (12.1%), histone modification (9.1%), and chromatin changes (4.5%). Nine (13.6%) reports examined the discrepancy of epigenetic signatures between subjects or tissues with and without VC, supporting their applicability as biomarkers. Assisted by bioinformatic analyses blending in each epigenetic component, we discovered prominent interactions between microRNAs, DNA methylation, and histone modification regarding potential influences on VC risk.

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Cellular Senescence in Bone

10.5772/intechopen.101803 ◽

2021 ◽

Author(s):

Danielle Wang ◽

Haitao Wang

Keyword(s):

Cellular Senescence ◽

Bone Diseases ◽

Epigenetic Alterations ◽

Pharmacological Interventions ◽

Telomere Attrition ◽

Cycle Arrest ◽

Age Related ◽

The Common ◽

Common Problems

Senescence is an irreversible cell-cycle arrest process induced by environmental, genetic, and epigenetic factors. An accumulation of senescent cells in bone results in age-related disorders, and one of the common problems is osteoporosis. Deciphering the basic mechanisms contributing to the chronic ailments of aging may uncover new avenues for targeted treatment. This review focuses on the mechanisms and the most relevant research advancements in skeletal cellular senescence. To identify new options for the treatment or prevention of age-related chronic diseases, researchers have targeted hallmarks of aging, including telomere attrition, genomic instability, cellular senescence, and epigenetic alterations. First, this chapter provides an overview of the fundamentals of bone tissue, the causes of skeletal involution, and the role of cellular senescence in bone and bone diseases such as osteoporosis. Next, this review will discuss the utilization of pharmacological interventions in aging tissues and, more specifically, highlight the role of senescent cells to identify the most effective and safe strategies.

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The telomere complex and the origin of the cancer stem cell

Biomarker Research ◽

10.1186/s40364-021-00339-z ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

A. Torres-Montaner

Keyword(s):

Stem Cells ◽

Malignant Transformation ◽

Developmental Stages ◽

Telomere Maintenance ◽

Leukemia Stem Cells ◽

Self Renewal ◽

Telomere Attrition ◽

Oncogenic Pathways ◽

Tumor Protection

AbstractExquisite regulation of telomere length is essential for the preservation of the lifetime function and self-renewal of stem cells. However, multiple oncogenic pathways converge on induction of telomere attrition or telomerase overexpression and these events can by themselves trigger malignant transformation. Activation of NFκB, the outcome of telomere complex damage, is present in leukemia stem cells but absent in normal stem cells and can activate DOT1L which has been linked to MLL-fusion leukemias. Tumors that arise from cells of early and late developmental stages appear to follow two different oncogenic routes in which the role of telomere and telomerase signaling might be differentially involved. In contrast, direct malignant transformation of stem cells appears to be extremely rare. This suggests an inherent resistance of stem cells to cancer transformation which could be linked to a stem cell’specific mechanism of telomere maintenance. However, tumor protection of normal stem cells could also be conferred by cell extrinsic mechanisms.

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Superresolution imaging reveals spatiotemporal propagation of human replication foci mediated by CTCF-organized chromatin structures

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2001521117 ◽

2020 ◽

Vol 117 (26) ◽

pp. 15036-15046 ◽

Cited By ~ 1

Author(s):

Qian Peter Su ◽

Ziqing Winston Zhao ◽

Luming Meng ◽

Miao Ding ◽

Weiwei Zhang ◽

...

Keyword(s):

Dna Replication ◽

S Phase ◽

Replication Origins ◽

Nuclear Dynamics ◽

Superresolution Imaging ◽

Stochastic Optical Reconstruction Microscopy ◽

Replication Foci ◽

Optical Reconstruction ◽

Epigenetic Signatures

Mammalian DNA replication is initiated at numerous replication origins, which are clustered into thousands of replication domains (RDs) across the genome. However, it remains unclear whether the replication origins within each RD are activated stochastically or preferentially near certain chromatin features. To understand how DNA replication in single human cells is regulated at the sub-RD level, we directly visualized and quantitatively characterized the spatiotemporal organization, morphology, and in situ epigenetic signatures of individual replication foci (RFi) across S-phase at superresolution using stochastic optical reconstruction microscopy. Importantly, we revealed a hierarchical radial pattern of RFi propagation dynamics that reverses directionality from early to late S-phase and is diminished upon caffeine treatment or CTCF knockdown. Together with simulation and bioinformatic analyses, our findings point to a “CTCF-organized REplication Propagation” (CoREP) model, which suggests a nonrandom selection mechanism for replication activation at the sub-RD level during early S-phase, mediated by CTCF-organized chromatin structures. Collectively, these findings offer critical insights into the key involvement of local epigenetic environment in coordinating DNA replication across the genome and have broad implications for our conceptualization of the role of multiscale chromatin architecture in regulating diverse cell nuclear dynamics in space and time.

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Epigenetic correlates of neonatal contact in humans

Development and Psychopathology ◽

10.1017/s0954579417001213 ◽

2017 ◽

Vol 29 (5) ◽

pp. 1517-1538 ◽

Cited By ~ 26

Author(s):

Sarah R. Moore ◽

Lisa M. McEwen ◽

Jill Quirt ◽

Alex Morin ◽

Sarah M. Mah ◽

...

Keyword(s):

Receptor Gene ◽

Infant Distress ◽

Epigenetic Age ◽

Early Human Development ◽

Glucocorticoid Receptor Gene ◽

Tactile Contact ◽

Μ Opioid Receptor ◽

Epigenetic Signatures ◽

Nuclear Receptor Subfamily

AbstractAnimal models of early postnatal mother–infant interactions have highlighted the importance of tactile contact for biobehavioral outcomes via the modification of DNA methylation (DNAm). The role of normative variation in contact in early human development has yet to be explored. In an effort to translate the animal work on tactile contact to humans, we applied a naturalistic daily diary strategy to assess the link between maternal contact with infants and epigenetic signatures in children 4–5 years later, with respect to multiple levels of child-level factors, including genetic variation and infant distress. We first investigated DNAm at four candidate genes: the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), μ-opioid receptor M1 (OPRM1) and oxytocin receptor (OXTR; related to the neurobiology of social bonds), and brain-derived neurotrophic factor (BDNF; involved in postnatal plasticity). Although no candidate gene DNAm sites significantly associated with early postnatal contact, when we next examined DNAm across the genome, differentially methylated regions were identified between high and low contact groups. Using a different application of epigenomic information, we also quantified epigenetic age, and report that for infants who received low contact from caregivers, greater infant distress was associated with younger epigenetic age. These results suggested that early postnatal contact has lasting associations with child biology.

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Telomeres and Aging

Physiological Reviews ◽

10.1152/physrev.00026.2007 ◽

2008 ◽

Vol 88 (2) ◽

pp. 557-579 ◽

Cited By ~ 626

Author(s):

Geraldine Aubert ◽

Peter M. Lansdorp

Keyword(s):

Telomere Length ◽

Cell Fate ◽

Cellular Response ◽

Genome Instability ◽

Somatic Cells ◽

Growth Stimulation ◽

Dyskeratosis Congenita ◽

Telomere Attrition ◽

Response To Stress

Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must “cap” each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or “uncapped” telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many “uncapped” telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed.

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