A GADD45α-ING1-C/EBP axis regulates energy homeostasis and organismal aging
- Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
- 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.