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.
authors: 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.
authors: Dana
authors: D
authors: Avrahami
authors: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Changhong
authors: C
authors: Li
authors: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Jia
authors: J
authors: Zhang
authors: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Jonathan
authors: J
authors: Schug
authors: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Ran
authors: R
authors: Avrahami
authors: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Shilpa
authors: S
authors: Rao
authors: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors: Michael B
authors: MB
authors: Stadler
authors: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors: Lukas
authors: L
authors: Burger
authors: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors: Dirk
authors: D
authors: Schübeler
authors: Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Benjamin
authors: B
authors: Glaser
authors: 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.
authors: Klaus H
authors: KH
authors: Kaestner
mesh_terms: D000375:Aging; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D007328:Insulin; D014157:Transcription Factors