Impaired DNA demethylation of C/EBP sites causes premature aging

Genes Dev. 2018 Jun 1;32(11-12):742-762. doi: 10.1101/gad.311969.118. Epub 2018 Jun 8.

Abstract

Changes in DNA methylation are among the best-documented epigenetic alterations accompanying organismal aging. However, whether and how altered DNA methylation is causally involved in aging have remained elusive. GADD45α (growth arrest and DNA damage protein 45A) and ING1 (inhibitor of growth family member 1) are adapter proteins for site-specific demethylation by TET (ten-eleven translocation) methylcytosine dioxygenases. Here we show that Gadd45a/Ing1 double-knockout mice display segmental progeria and phenocopy impaired energy homeostasis and lipodystrophy characteristic of Cebp (CCAAT/enhancer-binding protein) mutants. Correspondingly, GADD45α occupies C/EBPβ/δ-dependent superenhancers and, cooperatively with ING1, promotes local DNA demethylation via long-range chromatin loops to permit C/EBPβ recruitment. The results indicate that enhancer methylation can affect aging and imply that C/EBP proteins play an unexpected role in this process. Our study suggests a causal nexus between DNA demethylation, metabolism, and organismal aging.

Keywords: Cebp; E2F; adipogenesis; aging; chromatin looping; progeria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Aging, Premature / genetics*
  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics*
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cells, Cultured
  • DNA Demethylation*
  • Homeostasis / genetics
  • Inhibitor of Growth Protein 1 / genetics
  • Inhibitor of Growth Protein 1 / metabolism*
  • Lipodystrophy / genetics
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Cell Cycle Proteins
  • Gadd45a protein, mouse
  • Inhibitor of Growth Protein 1
  • Nuclear Proteins