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

doi:10.1016/j.cmet.2015.07.025

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

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

145 Scopus citations

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.

Original language	American English
Pages (from-to)	619-632
Number of pages	14
Journal	Cell Metabolism
Volume	22
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2015.07.025
State	Published - 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).

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© 2015 Elsevier Inc.

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10.1016/j.cmet.2015.07.025

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

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.",

author = "Dana Avrahami and Changhong Li and Jia Zhang and Jonathan Schug and Ran Avrahami and Shilpa Rao and Stadler, {Michael B.} and Lukas Burger and Dirk Sch{\"u}beler and Benjamin Glaser and Kaestner, {Klaus H.}",

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: {\textcopyright} 2015 Elsevier Inc.",

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AU - Avrahami, Ran

AU - Rao, Shilpa

AU - Stadler, Michael B.

AU - Burger, Lukas

AU - Schübeler, Dirk

AU - Glaser, Benjamin

AU - Kaestner, Klaus H.

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N2 - 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.

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

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