The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
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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“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
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“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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DAVID: Database for Annotation, Visualization, and Integrated Discovery
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DNA methylation patterns and epigenetic memory
Bird, A. (2002) · Genes & Development · doi:10.1101/gad.947102 · Cited by 7,124
Histone H3K27ac separates active from poised enhancers and predicts developmental state
Creyghton, M. P., Cheng, A. W., Welstead, G. G., Kooistra, T., Carey, B. W., Steine, E. J., Hanna, J., Lodato, M. A., Frampton, G. M., Sharp, P. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016071107 · Cited by 4,302
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“We integrated all significant DMRs with our whole genome histone modification maps from old and young b cells, including H3K4me1, which is enriched in nucleosomes that occupy potential enhancers (Heintzman et al., 2007) and H3K27me3, associated with transcriptionally silent chromatin (Schubert et al.”
Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA
He, Y., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., et al. (2011) · Science · doi:10.1126/science.1210944 · Cited by 2,776
Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation
Dor, Y., Brown, J., Martinez, O. I., & Melton, D. A. (2004) · Nature · doi:10.1038/nature02520 · Cited by 2,219
DNA-binding factors shape the mouse methylome at distal regulatory regions
Stadler, M. B., Murr, R., Burger, L., Ivanek, R., Lienert, F., Schöler, A., Nimwegen, E. V., Wirbelauer, C., Oakeley, E. J., Gaidatzis, D., et al. (2011) · Nature · doi:10.1038/nature10716 · Cited by 1,383
Self-citationp16INK4a induces an age-dependent decline in islet regenerative potential
Krishnamurthy, J., Ramsey, M. R., Ligon, K. L., Torrice, C., Koh, A., Bonner-Weir, S., & Sharpless, N. E. (2006) · Nature · doi:10.1038/nature05092 · Cited by 1,003 · cited 1×
“Conversely, we observed reduced expression of genes governing b cell proliferation such as the cyclin D genes and CDKs and elevated expression of the cell-cycle inhibitor p16 (encoded by Cdkn2a; Table S5), previously shown to contribute to loss of b cell replicationwith aging (Krishnamurthy et al., 2006).”
Meier, J. J., Butler, A. E., Saisho, Y., Monchamp, T., Galasso, R., Bhushan, A., Rizza, R. A., & Butler, P. C. (2008) · Diabetes · doi:10.2337/db07-1369 · Cited by 683
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Mawla, A. M., van der Meulen, T., & Huising, M. O. (2023) · Figshare · doi:10.6084/m9.figshare.22649510
Mawla, A. M., van der Meulen, T., & Huising, M. O. (2023) · Figshare · doi:10.6084/m9.figshare.22649516
Mawla, A. M., van der Meulen, T., & Huising, M. O. (2023) · Figshare · doi:10.6084/m9.figshare.22649495
Islet cell DNA methylation in human ageing and diabetes
Hodges, E. C., & Gu, G. (2026) · Nature Metabolism · doi:10.1038/s42255-026-01502-2
Diaz-Herreros, A. N., Reyes‐Maldonado, E., Rosales-Cruz, É., Gómez‐Chávez, F., Valdez-Guerrero, A. S., Rodríguez‐Cortés, O., Cancino‐Díaz, J. C., & Cancino-Diaz, M. E. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27104640
Tudurí, E., Almagro, L., Ojeda‐Rodríguez, A., Pascua‐Maestro, R., Brunetta, H. S., Soriano, S., López‐Moreno, A., Boronat‐Belda, T., Velasco-Avilés, S., da Silva, J. A., et al. (2026) · Aging Cell · doi:10.1111/acel.70753
Metadata
- 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 › Endocrinology, Diabetes and Metabolism › 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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