Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging
Open accessAbstract
The functional potential of hematopoietic stem cells (HSCs) declines during aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs during ontogeny in combination with functional analysis. Although the DNA methylome is generally stable during aging, site-specific alterations of DNA methylation occur at genomic regions associated with hematopoietic lineage potential and selectively target genes expressed in downstream progenitor and effector cells. We found that age-associated HSC decline, replicative limits, and DNA methylation are largely dependent on the proliferative history of HSCs, yet appear to be telomere-length independent. Physiological aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging.
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Several genome-wide studies have not found a correlation between age-dependent differential DNA methylation and altered gene expression.
“Surprisingly, several genome-wide studies have not found a correlation between age-dependent differential DNA methylation and altered gene expression (Beerman et al., 2013; Yuan et al., 2015).”
From The Aging Epigenome (2016) · cites this paper as Beerman et al., 2013
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 Beerman et al., 2013
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 Beerman et al., 2013
DNA methylation tends to increase with age at some CpG islands, particularly at polycomb target genes and at promoters of tumour suppressor genes.
“DNA methylation tends to increase with age at some CpG islands, particularly at polycomb target genes 55,56 and at promoters of tumour suppressor genes 57 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [57]
A limited number of genomic loci gain DNA methylation during ageing and in cancer, in particular CpG islands in promoters of tumour suppressor genes and polycomb targets.
“A limited number of genomic loci gain DNA methylation during ageing and in cancer, in particular CpG islands in promoters of tumour suppressor genes (TSGs) and polycomb targets 57 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [57]
Donor-derived reconstitution from old HSCs is significantly lower than from young HSCs and shows a marked myeloid bias.
“examination of donor-derived reconstitution from old HSCs was significantly lower compared to the young with a marked myeloid bias lineage output”
From Quiescent Hematopoietic Stem Cells Accumulate DNA Damage during Aging that Is Repaired upon Entry into Cell Cycle (2014) · cites this paper as Beerman et al., 2013
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Self-citation
- Authors
- Beerman, I., Bock, C., Garrison, B. S., Smith, Z. D., Gu, H., Meissner, A., & Rossi, D. J.
- Affiliations
- Boston Children's Hospital (US)
- Broad Institute (US)
- Corresponding author
- Meissner, Alexander
- Rossi, Derrick J.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 12
- Issue
- 4
- Pages
- 413-425
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC12163706
- OpenAlex
- W2142053177
- Cited by
- 485
- References
- 60
- Citations by year
- 2026: 26 · 2025: 26 · 2024: 38 · 2023: 33 · 2022: 29 · 2021: 31 · 2020: 46 · 2019: 27 · 2018: 49 · 2017: 40 · 2016: 44 · 2015: 43 · 2014: 34 · 2013: 19
- FWCI
- 33.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Pew Charitable Trusts
- New York Stem Cell Foundation
- National Institutes of Health (Z99 AG999999)
- Harvard Stem Cell Institute
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- hematopoietic stem cells, stem cell aging, DNA methylation, epigenetic aging, cell proliferation, polycomb repressive complex 2, telomere length, hematopoietic progenitor cells, DNA hypermethylation
- MeSH terms
- Animals, DNA Replication, Hematopoiesis, Hematopoietic Stem Cells, Male, Mice, Inbred C57BL, Models, Biological, Telomere, Cellular Senescence, Gene Expression Regulation, Developmental, DNA Methylation, Cell Proliferation, Mice, Polycomb Repressive Complex 2
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