6533b825fe1ef96bd1282902
RESEARCH PRODUCT
Impaired DNA demethylation of C/EBP sites causes premature aging
Medhavi MallickAndrea I. SchäferBernadette MekkerDominik SebastianChristof NiehrsEmil KaraulanovDamien J. DownesCarola ScholzBernd EpeCarina Von Der LippenViviana Vastolosubject
0301 basic medicinePremature agingAgingLipodystrophyDNA damageCell Cycle ProteinsBiology03 medical and health sciencesMiceGeneticsAnimalsHomeostasisEpigeneticsCells CulturedDemethylationMice KnockoutNuclear ProteinsAging PrematureMethylationCell biologyChromatinDNA Demethylation030104 developmental biologyDNA demethylationDNA methylationCCAAT-Enhancer-Binding ProteinsInhibitor of Growth Protein 1Developmental BiologyResearch Paperdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-06-01 |