A hyper-quiescent chromatin state formed during aging is reversed by regeneration
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE223480 | GEO | 2023/03/17
REPOSITORIES: GEO
Similar Datasets
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.
2023-03-17 | GSE185704 | GEO
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
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.
2023-03-19 | GSE185707 | GEO
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 | GSE185705 | GEO
Project description:Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. While it is well established that many of the age-induced changes are intrinsic to HSCs, less is known about the stability of this state. Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations. To examine this issue at a functional level in vivo, we applied induced pluripotent stem (iPS) cell reprogramming of aged hematopoietic progenitors and allowed the resulting aged-derived iPS cells to reform hematopoiesis via blastocyst complementation. Next, we functionally characterized iPS-derived HSCs in primary chimeras and following the transplantation of 're-differentiated' HSCs into new hosts; the gold standard to assess HSC function. Our data demonstrate remarkably similar functional properties of iPS-derived and endogenous blastocyst-derived HSCs, despite the extensive chronological and proliferative age of the former. Our results therefore favor a model in which an underlying, but reversible, epigenetic component is a hallmark of HSC aging rather than being driven by an increased DNA mutation burden. Hematopoietic stem cells (HSC) have been sorted out from young and aged steady-state mice, and from recipients transplanted with young and aged bone marrow. Generated iPS and commercially available ES cells were also sorted and analyzed.
2013-03-06 | E-GEOD-44923 | biostudies-arrayexpress
Project description:Sustained exposure to a young systemic environment rejuvenates aged tissues and promotes stem cell function. However, due to the intrinsic complexity of tissues it remains challenging to pinpoint direct effects of circulating factors on specific cell populations. Here we describe a method for the encapsulation of human stem cells in highly diffusible polyethersulfone hollow fiber capsules that can be used to profile systemic aging independent of physical cellular interactions in-vivo.
2022-03-05 | GSE111401 | GEO
Project description:Senescence-associated alterations in microglia may have profound impact on cerebral homeostasis and stroke outcomes. However, the lack of a transcriptome-wide comparison between young and aged microglia in the context of ischemia limits our understanding of aging-related mechanisms. Herein, we performed bulk RNA sequencing analysis of microglia purified from cerebral hemispheres of young adult (10-week-old) and aged (18-month-old) mice 5 days after distal middle cerebral artery occlusion or sham operation. Considerable transcriptional differences were observed between young and aged microglia in healthy brains, indicating heightened chronic inflammation in aged microglia. Following stroke, the overall transcriptional activation was more robust in young microglia than in aged microglia. Gene clusters with functional implications in immune inflammatory responses, immune cell chemotaxis, tissue remodeling, and cell-cell interactions were markedly activated in microglia of young but not aged stroke mice. These alterations in microglial gene response may contribute to aging-driven vulnerability and poorer recovery after ischemic stroke.
2020-05-31 | GSE145265 | GEO
Project description:Myelin aging is a driving force of CNS aging, and age-dependent declined efficiency of remyelination caused by impaired differentiation capacity of aged oligodendrocyte precursor cell (OPC) is a major cause of demyelinated diseases. Revealing how differentiation capacity of aged OPC is affected metabolically holds the key to find new way to rejuvenate the aged OPC. Here we screened out that NAD+ is one of the top metabolites impaired in premature aging OPC. Supplementing β-nicotinamide mononucleotide (β-NMN), an immediate NAD+ precursor, delays CNS myelin aging, promotes differentiation of aged OPC, and therapeutically and preventively rejuvenates remyelination in the aged CNS both ultra-structurally and functionally. To explore the molecular mechanisms underlying the enhancing remyelination by NAD+ supplementation, using LC-MS we investigated the changes of proteome differentially regulated by NAD+ or DMSO in cultured OPC from P0 rat brain.
2020-10-18 | PXD022046 | iProX
Project description:Sustained exposure to a young systemic environment rejuvenates aged organisms and promotes cellular function. However, due to the intrinsic complexity of tissues it remains challenging to pinpoint niche-independent effects of circulating factors on specific cell populations. Here we describe a method for the encapsulation of human and mouse skeletal muscle progenitors in diffusible polyethersulfone hollow fiber capsules that can be used to profile systemic aging in vivo independent of heterogeneous short-range tissue interactions. We observed that circulating long-range signaling factors in the old systemic environment lead to an activation of Myc and E2F transcription factors, induce senescence and suppress myogenic differentiation. Importantly, in vitro profiling using young and old serum in 2D culture does not capture all pathways deregulated in encapsulated cells in aged mice. Thus, in vivo transcriptomic profiling using cell encapsulation allows for the characterization of effector pathways of systemic aging with unparalleled accuracy.
2022-03-05 | GSE193665 | GEO
Project description:Aging at the cellular level is driven by changes in gene activity and epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic ? cell, key player in glucose homeostasis and diabetes, in adolescent and very old mice. Globally, we observe a general methylation drift resulting in an overall more leveled methylome, suggesting that the maintenance of highly differential methylation patterns becomes compromised with advanced age. Importantly, we discover targeted changes in the methylation status of ? cell proliferation and function genes that go against the global methylation drift, are specific to ? cells, and correlate with repression of the proliferation program and activation of metabolic regulators. These targeted alterations frequently occur at distal cis-regulator elements, and are associated with specific chromatin marks and transcription factor occupancy in young ? cells. Strikingly, we find the insulin secretory response to glucose much improved in mature ? cells in mice, as predicted by the changes in methylome and transcriptome and in contrast to the decline in function observed in aged human ? cells. Thus, aging of terminally differentiated cells in mammals is not always coupled to functional decline. RNA-seq was done on 3 biological replicas from old and three from young beta cells. each sample originated from a pool of 5-10 mic.e H3K27me3 ChIP-seq was done with two replicas for old mice (pool of 4-7 mice) and the rest of the ChIPseq (H3K4me1, H3K27ac and young H3K27me3) was sone with one sample (pool of few mice). BIS-seq was done on one sample from a pool of 10 young mice and one sample of a pool of old mice (18-22 months old)
2015-09-01 | E-GEOD-68618 | biostudies-arrayexpress