Histone Methyltransferase DOT1L Regulates Brown Adipocyte Differentiation and Thermogenesis

Brown fat has been extensively studied due to its potential in therapies against obesity. Various epigenetic regulators have been shown to modulate brown fat development and function. Here we show that histone methyltransferase DOT1L is a key regulator of brown adipocyte differentiation and thermogenesis. In vitro, we demonstrate that inhibition by DOT1L inhibitor or knockdown of DOT1L markedly promotes brown adipocyte differentiation of C3H10T1/2 cells. Moreover, depletion of DOT1L enhances differentiation and thermogenesis of primary brown adipocytes which separated from DOT1LFlox/Flox mice by transfection with Cre-expressing lentiviruses ex vivo. Mechanistically, knockdown of DOT1L results in increased expression of brown-selective genes, and the expression of brown preadipocyte maker EBF2 is significantly increased due to knockdown of DOT1L at early stage. Furthermore, ChIP assays suggest that DOT1L-mediated H3K79 methylations are negatively associated with transcription of UCP1 and PRDM16. Finally, we observe that the skin surface temperature in interscapular area of DOT1LMyf5 knockout mice is significantly higher. Notably, energy expenditure and the oxygen consumption rate are also increased in knockout mice. These in vivo data suggest that DOT1L depletion leads to enhanced thermogenic function of brown fat. Collectively, our work indicates that DOT1L plays an important role in regulating brown fat differentiation and thermogenesis, and provides another linkage between epigenetics and brown fat development and function. Disclosure L. Shuai: None. J. Li: None. J. Li: None. Funding China Postdoctoral Science Foundation