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Download fileDOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation
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posted on 2021-04-01, 14:13 authored by Lin Shuai, Bo-Han Li, Hao-Wen Jiang, Lin Yang, Jia Li, Jing-Ya LiBrown
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 in vivo. Loss of DOT1L in primary
preadipocytes significantly promotes brown and beige adipogenesis and
thermogenesis in vitro. 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.