DNMT1 maintains metabolic fitness of adipocytes through acting as an epigenetic safeguard of mitochondrial dynamics
Yoon Jeong Park, Sangseon Lee, Sangsoo Lim, Hahn Nahmgoong, Yul Ji, Jin Young Huh, Assim A. Alfadda, Sun Kim, Jae Bum Kim
Abstract
Significance Adipose tissue dysfunction is a major pathogenic determinant of obesity and related metabolic disorders. Although DNA methylation is one of the crucial epigenetic modifications in adipocytes, the molecular determinant and its roles in maintaining adipocyte function remain elusive. Here, we show that DNA methylation directs distal enhancer-mediated transcriptomic features of adipocytes. Particularly, deletion of adipocyte Dnmt1, the major methylation writer, provokes adipocyte hypertrophy and defective glucose homeostasis. Mechanistically, adipocyte Dnmt1 is crucial for preventing aberrant CTCF binding to sustain the proper chromosome architecture required for interactions between enhancer and Dnm1l and, in turn, facilitates mitochondrial fission and lipid homeostasis. Thus, we identify Dnmt1 as a key epigenetic safeguard of adipocyte integrity, which could have therapeutic implications for metabolic diseases.