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Cell Metab. 2015 Oct 6;22(4):619-32. doi: 10.1016/j.cmet.2015.07.025. Epub 2015 Aug 27.

Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function.

Author information

1
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
2
Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
3
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
4
Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
5
Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
6
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: kaestner@mail.med.upenn.edu.

Abstract

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.

PMID:
26321660
PMCID:
PMC4598285
DOI:
10.1016/j.cmet.2015.07.025
[Indexed for MEDLINE]
Free PMC Article

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