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A hyper-quiescent chromatin state is a barrier to productive regeneration during aging. [DNA-Seq]

ABSTRACT: Epigenetic alterations are one of the key hallmarks of aging. Emerging evidence in model organisms, senescent cell cultures and limitedly, murine, and human tissue samples suggest local effects impacting genes and regulatory elements. However, how chromatin changes broadly affect euchromatin-heterochromatin balance, three-dimensional chromatin conformation, histone composition and global transcriptome has not been addressed. Furthermore, the cause and impact of these alterations on tissue function and age-related loss of regeneration is not well-understood. Here, using murine liver as a model for regeneration and an integrated multi-omics approach, we find that aged cells assume a severely repressed hyper-quiescent chromatin state characterized by a condensed chromatin, broad heterochromatinization driven by H3K27me3, global suppression of the transcriptome and inability of the chromatin to self-interact over long distances. Interestingly, concomitant targeted chromatin opening occurs over developmental gene promoters leading to loss of cell identity. We extend our findings to other quiescent tissues including human liver biopsies. Our findings reveal that global chromatin alterations promote a cellular state that is refractory to injury sensing and repair. Local chromatin changes compromise cellular identity. Together, this study provides possible explanations for age-related loss of regeneration and tissue function at the chromatin level.

ORGANISM(S): Mus musculus

PROVIDER: GSE185707 | GEO | 2023/03/19

REPOSITORIES: GEO

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A hyper-quiescent chromatin state is a barrier to productive regeneration during aging. [CUT&Tag ]

Project description:Epigenetic alterations are one of the key hallmarks of aging. Emerging evidence in model organisms, senescent cell cultures and limitedly, murine, and human tissue samples suggest local effects impacting genes and regulatory elements. However, how chromatin changes broadly affect euchromatin-heterochromatin balance, three-dimensional chromatin conformation, histone composition and global transcriptome has not been addressed. Furthermore, the cause and impact of these alterations on tissue function and age-related loss of regeneration is not well-understood. Here, using murine liver as a model for regeneration and an integrated multi-omics approach, we find that aged cells assume a severely repressed hyper-quiescent chromatin state characterized by a condensed chromatin, broad heterochromatinization driven by H3K27me3, global suppression of the transcriptome and inability of the chromatin to self-interact over long distances. Interestingly, concomitant targeted chromatin opening occurs over developmental gene promoters leading to loss of cell identity. We extend our findings to other quiescent tissues including human liver biopsies. Our findings reveal that global chromatin alterations promote a cellular state that is refractory to injury sensing and repair. Local chromatin changes compromise cellular identity. Together, this study provides possible explanations for age-related loss of regeneration and tissue function at the chromatin level.

2023-03-17 | GSE185703 | GEO

A hyper-quiescent chromatin state is a barrier to productive regeneration during aging. [RNA-Seq]

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A hyper-quiescent chromatin state formed during aging is reversed by regeneration [ChIP-seq]

Project description:Epigenetic alterations are a key hallmark of aging but have not been extensively explored in tissues. Here, using naturally aged murine liver as a model and extending study to other quiescent tissues, we find that aging is driven by temporal chromatin alterations that promote a refractory cellular state and compromise cellular identity. Using an integrated multi-omics approach and the first direct visualization of aged chromatin, we find that old cells show global H3K27me3-driven broad heterochromatinization and transcription suppression. At the local level, site-specific loss of H3K27me3 from promoters of genes encoding developmental transcription factors leads to expression in liver of non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver.

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

2023-03-17 | GSE223480 | GEO

Niche stiffening compromises stem cell potential during aging by reducing chromatin accessibility at bivalent promoters

Project description:Tissue homeostasis and regeneration require activation and subsequent lineage commitment of tissue-resident stem cells (SCs). These state changes are controlled by epigenetic barriers. Using hair follicle stem cells (HFSCs) as paradigm, we studied how aging impacts the chromatin landscape and function of mammalian SCs. Analyses of genome-wide chromatin accessibility revealed that aged HFSCs displayed widespread reduction of chromatin accessibility specifically at key SC self-renewal and differentiation genes that were characterized by bivalent promoters carrying both activating and repressive chromatin marks. Consistently, aged HFSCs showed reduced self-renewing capacity and attenuated ability to activate expression of these bivalent genes upon regeneration. These functional defects were niche-dependent as transplantation of aged HFSCs into young recipients or into ex vivo niches restored SC functions and transcription of poised genes. Mechanistically, aged HFSC niche displayed wide-spread alterations in extracellular matrix composition and mechanics, resulting in compressive forces on SCs and subsequent transcriptional repression, leading to loss of bivalent promoters. Tuning tissue mechanics both in vivo and in vitro recapitulated age-related SC changes, implicating niche mechanics as a central regulator of genome organization and function leading to age-dependent SC exhaustion.

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Fibrogenic cell plasticity blunts tissue regeneration and aggravates muscular dystrophy

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Foxc1 reinforces quiescence in hair follicle stem cells

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