Open AccessImpaired DNA demethylation of C/EBP sites causes premature aging
Author(s) -
Andrea Schäfer,
Bernadette Mekker,
Medhavi Mallick,
Viviana Vastolo,
Emil Karaulanov,
Dominik Sebastian,
Carina von der Lippen,
Bernd Epe,
Damien J. Downes,
Carola Scholz,
Christof Niehrs
Publication year - 2018
Publication title -
genes and development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.136
H-Index - 438
eISSN - 1549-5477
pISSN - 0890-9369
DOI - 10.1101/gad.311969.118
Subject(s) - biology , dna methylation , epigenetics , dna demethylation , premature aging , chromatin , dna damage , ccaat enhancer binding proteins , microbiology and biotechnology , phenocopy , dna repair , genetics , dna , nuclear protein , mutant , gene , transcription factor , gene expression
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.