DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

Brown and beige adipocytes are characterized as thermogenic adipocytes and have great potential for treating obesity and associated metabolic diseases. Here, we identify a conserved mammalian lysine 79 of histone H3 (H3K79) methyltransferase, disruptor of telomeric silencing -1 like (DOT1L), as a new epigenetic regulator that controls thermogenic adipocyte differentiation and function. We show that deletion of DOT1L in thermogenic adipocytes potently protects mice from diet-induced obesity, improves glucose homeostasis, alleviates hepatic steatosis, and facilitates adaptive thermogenesis<i> in vivo</i>. Loss of DOT1L in primary preadipocytes significantly promotes brown and beige adipogenesis and thermogenesis<i> in vitro</i>. Mechanistically, DOT1L epigenetically regulates the BAT-selective gene program through modulating H3K79 methylation, in particular H3K79me2 modification. Thus, our study demonstrates that DOT1L exerts an important role in energy homeostasis by regulating thermogenic adipocyte differentiation and function.