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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging*
  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Chromatin / metabolism*
  • CpG Islands
  • DNA Methylation
  • Enhancer Elements, Genetic / genetics
  • Histones / genetics
  • Histones / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • Protein Binding
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism


  • Chromatin
  • Histones
  • Insulin
  • Transcription Factors

Associated data

  • GEO/GSE68618