Aging-dependent demethylation of regulatory elements correlates with chromatin state and improved β cell function

Dana Avrahami, Changhong Li, Jia Zhang, Jonathan Schug, Ran Avrahami, Shilpa Rao, Michael B. Stadler, Lukas Burger, Dirk Schübeler, Benjamin Glaser, Klaus H. Kaestner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

149 Scopus citations


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.

Original languageAmerican English
Pages (from-to)619-632
Number of pages14
JournalCell Metabolism
Issue number4
StatePublished - 6 Oct 2015

Bibliographical note

Funding Information:
We thank Drs. Yuval Dor, Marisa Bartolomei, Karyn Sheaffer, and Mitch Lazar for critical comments on the manuscript, Olga Smirnova, Haleigh Zillges, Christina Theodouru, and Tia Bernard for excellent technical support. This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (UC4DK104119 to K.H.K. and B.G.). D.A. was supported by NIDDK 5T32DK007314. We thank the University of Pennsylvania Diabetes Research Center (DRC) for the use of the Functional Genomics, Radioimmunoassay, and Islet Cell Biology Cores (P30-DK19525).

Publisher Copyright:
© 2015 Elsevier Inc.


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