A hyper-quiescent chromatin state formed during aging is reversed by regeneration

Yang, Na; Occean, James R.; Melters, Daniël P.; Shi, Changyou; Wang, Lin; Stransky, Stephanie; Doyle, Maı̀re E.; Cui, Chang‐Yi; Delannoy, Michaël; Fan, Jinshui; Slama, Eliza; Egan, Josephine M.; De, Supriyo; Cunningham, Steven C.; Cabo, Rafael de; Dalal, Yamini

doi:10.1101/2023.02.14.528512

Cited by 4 publications

(4 citation statements)

References 67 publications

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“…Our analysis also highlighted a number of homeobox genes -well-known master developmental control genes, some of which have roles in mammalian reproduction 22 . More generally, these developmental genes may be targets of polycomb-mediated H3K27me3 silencing, which commonly occurs in GC rich regions and mediates aging and cellular identity 23 . We also identi ed the FBKP11 gene, a negative regulator of the mammalian target of rapamycin (mTOR) pathway which is thought to play an important role in the onset of sexual maturation 21 .…”

Section: Discussionmentioning

confidence: 99%

Universal prediction of vertebrate species age at maturity

Budd,

Yong,

Heydenrych

et al. 2024

Preprint

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Animal age at maturity can be used as a universal and simple predictor of species extinction risk. At present, methods to estimate age at maturity are typically species-specific, limiting comparisons among species or are infeasible to do practical constraints. To overcome this, we developed a universal predictor of vertebrate species age at maturity. We show that the frequency of ‘CG’ sequences (CpG sites) in gene promoter regions is a rapid predictor of vertebrate age at maturity. Our models predict age at maturity with remarkable accuracy and generalisability, with median error rates of 30% (less than 1 year) and are robust to genome assemblies of varying quality. We generate age at maturity predictions for 1912 vertebrate species for which this information was previously absent from online databases and envisage these predictions will help to inform management decisions for the many species for which more detailed population information is currently unavailable.

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Section: Discussionmentioning

confidence: 99%

Universal prediction of vertebrate species age at maturity

Budd,

Yong,

Heydenrych

et al. 2024

Preprint

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“…The molecular mechanisms and causal relationships underlying age-related transcriptional changes and the loss of heterochromatin during aging has largely remained elusive. According to the "'heterochromatin loss" theory of aging, the degradation of constitutive heterochromatin at the nuclear periphery, marked by H3K9me3, is believed to play a pivotal role during the aging processes driving pro-aging cellular phenotypes (Kane and Sinclair, 2019;N. Yang et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Loss of H3K9 trimethylation leads to premature aging

Mrabti,

Yang,

Desdín-Micó

et al. 2024

Preprint

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SUMMARYAging is the major risk factor for most human diseases and represents a major socio-economical challenge for modern societies. Despite its importance, the process of aging remains poorly understood. Epigenetic dysregulation has been proposed as a key driver of the aging process. Modifications in transcriptional networks and chromatin structure might be central to age-related functional decline. A prevalent feature described during aging is the overall reduction in heterochromatin, specifically marked by the loss of repressive histone modification, Histone 3 lysine 9 trimethylation (H3K9me3). However, the role of H3K9me3 in aging, especially in mammals, remains unclear. Here we show using a novel mouse strain, (TKOc), carrying a triple knockout of three methyltransferases responsible for H3K9me3 deposition, that the inducible loss of H3K9me3 in adulthood results in premature aging. TKOc mice exhibit reduced lifespan, lower body weight, increased frailty index, multi-organ degeneration, transcriptional changes with significant upregulation of transposable elements, and accelerated epigenetic age. Our data strongly supports the concept that the loss of epigenetic information directly drives the aging process. These findings reveal the importance of epigenetic regulation in aging and suggest that interventions targeting epigenetic modifications could potentially slow down or reverse age-related decline. Understanding the molecular mechanisms underlying the process of aging will be crucial for developing novel therapeutic strategies that can delay the onset of age-associated diseases and preserve human health at old age specially in rapidly aging societies.

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“…H3K27me3 is simultaneously lost from promoters of genes encoding developmental transcription factors leading to ectopic expression of nonhepatocyte markers. During regeneration, these alterations reverse as cells re-enter the cell cycle [67 ▪▪ ]. Most of the aged cells in higher organisms tend towards this hyper-quiescent and nondividing state, potentially conferring antitumor properties.…”

Section: Programmed Vs Stochastic Epigenetic Changes During Aging And...mentioning

confidence: 99%

Epigenetic dynamics of aging and cancer development: current concepts from studies mapping aging and cancer epigenomes

Bisht,

Mao,

Easwaran

2024

Current Opinion in Oncology

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Purpose of review This review emphasizes the role of epigenetic processes as incidental changes occurring during aging, which, in turn, promote the development of cancer. Recent findings Aging is a complex biological process associated with the progressive deterioration of normal physiological functions, making age a significant risk factor for various disorders, including cancer. The increasing longevity of the population has made cancer a global burden, as the risk of developing most cancers increases with age due to the cumulative effect of exposure to environmental carcinogens and DNA replication errors. The classical ‘somatic mutation theory’ of cancer cause is being challenged by the observation that multiple normal cells harbor cancer driver mutations without resulting in cancer. In this review, we discuss the role of age-associated epigenetic alterations, including DNA methylation, which occur across all cell types and tissues with advancing age. There is an increasing body of evidence linking these changes with cancer risk and prognosis. Summary A better understanding about the epigenetic changes acquired during aging is critical for comprehending the mechanisms leading to the age-associated increase in cancer and for developing novel therapeutic strategies for cancer treatment and prevention.

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A hyper-quiescent chromatin state formed during aging is reversed by regeneration

Cited by 4 publications

References 67 publications

Universal prediction of vertebrate species age at maturity

Universal prediction of vertebrate species age at maturity

Loss of H3K9 trimethylation leads to premature aging

Epigenetic dynamics of aging and cancer development: current concepts from studies mapping aging and cancer epigenomes

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