Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function
Open accessAbstract
Aging is driven by changes of the epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic β cell, key player in glucose homeostasis, in adolescent and very old mice. We observe a global methylation drift resulting in an overall more leveled methylome in old β cells. Importantly, we discover targeted changes in the methylation status of β cell proliferation and function genes that go against the global methylation drift, are specific to β cells, and correlate with repression of the proliferation program and activation of metabolic regulators. These targeted alterations are associated with specific chromatin marks and transcription factor occupancy in young β cells. Strikingly, we find β cell function improved in aged mice, as predicted by the changes in methylome and transcriptome. Thus, aging of terminally differentiated cells in mammals is not always coupled to functional decline.
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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 Avrahami et al., 2015
In aged β cells, a significant correlation between DNA methylation and gene expression changes exists for distal regulatory regions (enhancers) but not proximal regulatory regions (promoters).
“However, at least in the case of aged β cells, a significant correlation between DNA methylation and gene expression changes exists for distal regulatory regions (enhancers), but not proximal regulatory regions (promoters) (Avrahami et al., 2015).”
From The Aging Epigenome (2016) · cites this paper as Avrahami et al., 2015
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- Authors
- Avrahami, D., Li, C., Zhang, J., Schug, J., Avrahami, R., Rao, S., Stadler, M. B., Burger, L., Schübeler, D., Glaser, B., & Kaestner, K. H.
- Affiliations
- Hadassah Medical Center (IL)
- Children's Hospital of Philadelphia (US)
- University of Pennsylvania (US)
- Friedrich Miescher Institute (CH)
- Corresponding author
- Kaestner, Klaus H.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 22
- Issue
- 4
- Pages
- 619-632
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4598285
- OpenAlex
- W2142976933
- Cited by
- 207
- References
- 33
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 16 · 2023: 27 · 2022: 14 · 2021: 23 · 2020: 13 · 2019: 20 · 2018: 21 · 2017: 24 · 2016: 26 · 2015: 3
- FWCI
- 10.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1uc4dk104119-01)
- U.S. Public Health Service (NIDDK 5T32DK007314)
- National Institute of Diabetes and Digestive and Kidney Diseases (UC4DK116271, UC4-DK104119, R01DK098517, P30 DK 19525, P30DK019525, T32DK007314)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- aging, DNA methylation, pancreatic beta cells, epigenetic drift, chromatin state, beta-cell function, beta-cell proliferation, glucose homeostasis, transcription factor occupancy, chromatin marks, transcriptome, terminal differentiation
- MeSH terms
- Insulin Secretion, Aging, Animals, Cells, Cultured, Chromatin, Enhancer Elements, Genetic, Histones, Insulin, Male, Mice, Inbred C57BL, Promoter Regions, Genetic, Protein Binding, Transcription Factors, CpG Islands, DNA Methylation, Cell Proliferation, Insulin-Secreting Cells, Mice
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