A GADD45α-ING1-C/EBP axis regulates energy homeostasis and organismal aging

Schäfer A1, Mekker B1, Mallick M1, Vastolo V1, Sebastian D1, Karaulanov E1 and Niehrs C1,2

  1. Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
  2. German Cancer Research Center (DKFZ), Division of Molecular Embryology, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.

Changes in DNA methylation are among the best-documented epigenetic alterations, which accompany aging. However, if and how altered DNA methylation is causally involved in aging has remained elusive. GADD45α and ING1 are adapter proteins for site-specific demethylation by TET methylcytosine dioxygenases. We show that Gadd45a/Ing1 double knockout mice (DKO) display premature aging and phenocopy impaired energy homeostasis and lipodystrophy, characteristic of Cebp (CCAAT/enhancer binding protein) mutants. Correspondingly, GADD45α occupies C/EBPβ/δ- dependent super-enhancers, and cooperatively with ING1 promotes local DNA demethylation to permit C/EBPβ recruitment. Our study reveals a causal nexus between DNA demethylation, metabolism and organismal aging.