Impaired DNA demethylation of C/EBP sites causes premature aging

  1. Christof Niehrs1,4
  1. 1Institute of Molecular Biology (IMB), 55128 Mainz, Germany;
  2. 2Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, 55128 Mainz, Germany;
  3. 3Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom;
  4. 4German Cancer Research Center, Division of Molecular Embryology, German Cancer Research Center–Center for Molecular Biology (DKFZ–ZMBH) Alliance, 69120 Heidelberg, Germany
  1. Corresponding authors: c.niehrs{at}imb-mainz.de, a.schaefer{at}imb-mainz.de
  1. 5 These authors contributed equally to this work.

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.

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Footnotes

  • Received January 22, 2018.
  • Accepted May 7, 2018.

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