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

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. [Display omitted] •DNA methylation of regulatory elements is dynamic with aging of pancreatic β cells•Promoters of pro-proliferation genes become de novo methylated with β cell aging•Enhancers near β cell function genes become demethylated with aging•Insulin secretory function increases with β cell maturation Aging is driven by epigenetic modifications only partially understood. Avrahami et al. show that targeted methylation changes in β cell genes correlate with repression of the proliferation program and activation of metabolic regulators. Strikingly, β cell function is improved in aged mice, as predicted by methylome and transcriptome changes.