Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal
Open accessAbstract
To investigate the cell-intrinsic aging mechanisms that erode the function of somatic stem cells during aging, we have conducted a comprehensive integrated genomic analysis of young and aged cells. We profiled the transcriptome, DNA methylome, and histone modifications of young and old murine hematopoietic stem cells (HSCs). Transcriptome analysis indicated reduced TGF-β signaling and perturbation of genes involved in HSC proliferation and differentiation. Aged HSCs exhibited broader H3K4me3 peaks across HSC identity and self-renewal genes and showed increased DNA methylation at transcription factor binding sites associated with differentiation-promoting genes combined with a reduction at genes associated with HSC maintenance. Altogether, these changes reinforce HSC self-renewal and diminish differentiation, paralleling phenotypic HSC aging behavior. Ribosomal biogenesis emerged as a particular target of aging with increased transcription of ribosomal protein and RNA genes and hypomethylation of rRNA genes. This data set will serve as a reference for future epigenomic analysis of stem cell aging.
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H3K4me3 deposition changes with age in murine hematopoietic stem cells, Drosophila, and cellular senescence in human fibroblasts.
“H3K4me3, a mark associated with active transcription, has also been implicated in longevity, and its deposition changes with age in murine hematopoietic stem cells and in Drosophila (Sun et al., 2014; Wood et al., 2010) and cellular senescence in human fibroblasts (Shah et al., 2013).”
From The Aging Epigenome (2016) · cites this paper as Sun et al., 2014
Age-associated changes in global H3K27me3 levels are context dependent.
“Interestingly, age-associated changes in global H3K27me3 levels are also context dependent.”
From The Aging Epigenome (2016) · cites this paper as Sun et al., 2014
In young vs old murine hematopoietic stem cells, H3K27me3 levels increased at most loci but decreased at some loci with age.
“A comparison of H3K27me3 deposition in young versus old murine hematopoietic stem cells revealed that while H3K27me3 levels increased at most loci, there were also loci with decreased H3K27me3 levels with age (Sun et al., 2014).”
From The Aging Epigenome (2016) · cites this paper as Sun et al., 2014
Age-associated DNA hypermethylation of some transcription factor binding sites suggests ability of these proteins to bind DNA and regulate transcription could be disrupted.
“For example, age-associated DNA hypermethylation of some transcription factor binding sites (Avrahami et al., 2015; Sun et al., 2014; Yuan et al., 2015) suggests that the ability of these proteins to bind DNA and regulate transcription could be disrupted.”
From The Aging Epigenome (2016) · cites this paper as Sun et al., 2014
Loci with age-associated DNA hypermethylation in stem cells are enriched for genes normally repressed by Polycomb repressive complex.
“Interestingly, studies in stem cells have also demonstrated that loci with age-associated DNA hypermethylation are enriched for genes normally repressed by Polycomb repressive complex, the complex that methylates H3K27 (Beerman et al., 2013; Sun et al., 2014; Teschendorff et al., 2010).”
From The Aging Epigenome (2016) · cites this paper as Sun et al., 2014
Age-related H3K4me2/3 deposition changes may alter KDM5/RBR-2 activation of key mitochondrial genes.
“changes in H3K4me2/3 deposition with age (Sun et al., 2014; Wood et al., 2010) may alter the ability of the H3K4me2/3 demethylase KDM5/RBR-2 to activate the transcription of key mitochondrial genes (Liu and Secombe, 2015).”
From The Aging Epigenome (2016) · cites this paper as Sun et al., 2014
Aged stem cell populations have a unique chromatin state and gene expression profile compared with youthful stem cells.
“Compared to youthful stem cells, aged stem cell populations have a unique chromatin state and gene expression profile (Beerman et al., 2013; Liu et al., 2013; Sun et al., 2014).”
From The Aging Epigenome (2016) · cites this paper as Sun et al., 2014
A general loss of histones and redistribution of methylation marks has been observed in yeast and human fibroblasts, suggesting an evolutionarily conserved mechanism that regulates replicative lifespan.
“A general loss of histones and redistribution of methylation marks has also been observed in yeast and human fibroblasts 70,71 , suggesting this is an evolutionarily conserved mechanism that regulates replicative lifespan [G] , but it remains unclear if replicative senescence also occurs in mammalian cells in vivo .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [71]
A general loss of histones is observed in replicative senescence.
“A general loss of histones is observed in replicative senescence 70,71”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [71]
In old HSCs, H3K4me3 increases across genes regulating self-renewal, in line with functional changes.
“By contrast, in old HSCs, H3K4me3 increases across genes regulating self-renewal, in line with functional changes99.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [99]
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- Authors
- Sun, D., Luo, M., Jeong, M., Rodriguez, B., Xia, Z., Hannah, R., Wang, H., Le, T., Faull, K. F., Chen, R., Gu, H., Bock, C., Meissner, A., Göttgens, B., Darlington, G. J., Li, W., & Goodell, M. A.
- Affiliations
- Baylor College of Medicine (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of California, Los Angeles (US)
- Broad Institute (US)
- Corresponding author
- Li, Wei
- Goodell, Margaret A.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 14
- Issue
- 5
- Pages
- 673-688
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4070311
- OpenAlex
- W2106462080
- Cited by
- 686
- References
- 65
- Citations by year
- 2026: 49 · 2025: 56 · 2024: 61 · 2023: 56 · 2022: 45 · 2021: 70 · 2020: 75 · 2019: 51 · 2018: 55 · 2017: 52 · 2016: 54 · 2015: 45 · 2014: 17
- FWCI
- 39.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Defense (T32 MH 19384-14, T32-HD007032, W81XWH-10-1-0501)
- Samuel Waxman Cancer Research Foundation (CPRIT RP110471, HG007538)
- Ellison Medical Foundation (RP110028)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- hematopoietic stem cells, stem cell aging, self-renewal, DNA methylation, histone modifications, H3K4me3, TGF-beta signaling, ribosome biogenesis, HSC differentiation, epigenetic profiling, transcriptome
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Hematopoietic Stem Cells, Male, Transforming Growth Factor beta, Cellular Senescence, Chromatin Immunoprecipitation, Mice, Epigenomics
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