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:10.1016/j.molcel.2023.04.005

Cited by 15 publications

(5 citation statements)

References 79 publications

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“…Whereas Yang N. and colleagues reported a generalized H3K27me3-associated heterochromatinization with aging 104 , here we describe more balanced, bidirectional H3K27me3 changes. Nonetheless, our results are in line with their observation that localized loss of H3K27me3 is associated with developmental gene promoters while gains of H3K27me3 are linked to H3K9me3 loss at lamin-associated domains 104 . We hypothesize that in the brain this latter phenomenon could be caused by the cellular re-repression, using facultative heterochromatin, of the constitutive heterochromatin loss during aging.…”

Section: Discussioncontrasting

confidence: 75%

“…3e, f ). This phenomenon of “chromatin switching”, which has some parallelisms with certain experimental models 76 – 78 , has very recently been described in the aging liver 104 . Whereas Yang N. and colleagues reported a generalized H3K27me3-associated heterochromatinization with aging 104 , here we describe more balanced, bidirectional H3K27me3 changes.…”

Section: Discussionmentioning

confidence: 58%

“…This phenomenon of “chromatin switching”, which has some parallelisms with certain experimental models 76 – 78 , has very recently been described in the aging liver 104 . Whereas Yang N. and colleagues reported a generalized H3K27me3-associated heterochromatinization with aging 104 , here we describe more balanced, bidirectional H3K27me3 changes. Nonetheless, our results are in line with their observation that localized loss of H3K27me3 is associated with developmental gene promoters while gains of H3K27me3 are linked to H3K9me3 loss at lamin-associated domains 104 .…”

Section: Discussionmentioning

confidence: 58%

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A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment

Pérez,

Tezanos,

Peñarroya

et al. 2024

Nat Commun

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Aging involves the deterioration of organismal function, leading to the emergence of multiple pathologies. Environmental stimuli, including lifestyle, can influence the trajectory of this process and may be used as tools in the pursuit of healthy aging. To evaluate the role of epigenetic mechanisms in this context, we have generated bulk tissue and single cell multi-omic maps of the male mouse dorsal hippocampus in young and old animals exposed to environmental stimulation in the form of enriched environments. We present a molecular atlas of the aging process, highlighting two distinct axes, related to inflammation and to the dysregulation of mRNA metabolism, at the functional RNA and protein level. Additionally, we report the alteration of heterochromatin domains, including the loss of bivalent chromatin and the uncovering of a heterochromatin-switch phenomenon whereby constitutive heterochromatin loss is partially mitigated through gains in facultative heterochromatin. Notably, we observed the multi-omic reversal of a great number of aging-associated alterations in the context of environmental enrichment, which was particularly linked to glial and oligodendrocyte pathways. In conclusion, our work describes the epigenomic landscape of environmental stimulation in the context of aging and reveals how lifestyle intervention can lead to the multi-layered reversal of aging-associated decline.

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Section: Discussioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 58%

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A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment

Pérez,

Tezanos,

Peñarroya

et al. 2024

Nat Commun

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“…A similar pattern was observed in the human brain, where H3.3 constituted >93% of the total H3 pool across individuals aged 14 to 72 years [125]. The accu-mulation of H3.3 was accompanied by an altered methylation landscape of tissue, reflecting the epigenetic plasticity in response to the association of different histone isoforms with the genome [126,127]. Furthermore, in fibroblasts and melanocytes, the proteolytic cleavage of H3.3 led to the integration of its cleaved product, known as H3.3cs1, into the nucleosome structure.…”

Section: Age-associated Replacement Of Canonical Isoforms By Histone ...supporting

confidence: 64%

“…Several reports demonstrated that H3.3 accumulated in aged and senescent cells, effectively replacing the H3.1 and H3.2 canonical histones. In the somatic tissues of mice, including the liver, kidney, heart, and brain, histone H3.3 progressively replaces the canonical histones, achieving near-saturation levels of neuronal nucleosomes by midadolescence [125][126][127]. A similar pattern was observed in the human brain, where H3.3 constituted >93% of the total H3 pool across individuals aged 14 to 72 years [125].…”

Section: Age-associated Replacement Of Canonical Isoforms By Histone ...mentioning

confidence: 68%

Unraveling Histone Loss in Aging and Senescence

Dubey,

Kleinman

2024

Cells

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As the global population experiences a notable surge in aging demographics, the need to understand the intricate molecular pathways exacerbated by age-related stresses, including epigenetic dysregulation, becomes a priority. Epigenetic mechanisms play a critical role in driving age-related diseases through altered gene expression, genomic instability, and irregular chromatin remodeling. In this review, we focus on histones, a central component of the epigenome, and consolidate the key findings of histone loss and genome-wide redistribution as fundamental processes contributing to aging and senescence. The review provides insights into novel histone expression profiles, nucleosome occupancy, disruptions in higher-order chromatin architecture, and the emergence of noncanonical histone variants in the aging cellular landscape. Furthermore, we explore the current state of our understanding of the molecular mechanisms of histone deficiency in aging cells. Specific emphasis is placed on highlighting histone degradation pathways in the cell and studies that have explored potential strategies to mitigate histone loss or restore histone levels in aging cells. Finally, in addressing future perspectives, the insights gained from this review hold profound implications for advancing strategies that actively intervene in modulating histone expression profiles in the context of cellular aging and identifying potential therapeutic targets for alleviating a multitude of age-related diseases.

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