EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex

Brown adipose tissue-enriched lysine methyltransferase EHMT1 is an essential enzyme in the PRDM16–C/EBP-β transcriptional complex that controls brown adipose cell fate and energy metabolism. Here it is shown that euchromatic histone-lysine N-methyltransferase 1 (EHMT1), an enzyme found at increased levels in brown adipose tissue (BAT), is an essential component of the PRDM16 transcriptional complex that controls brown adipose cell fate. Loss of EHMT1 in brown adipocytes results in loss of brown fat characteristics and induces muscle differentiation in vivo through demethylation of histone 3 Lys 9 in the muscle-selective gene promoters. By contrast, EHMT1 expression switches on the thermogenic gene program in brown adipocytes by stabilizing the PRDM16 protein. Adipose-specific deletion of EHMT1 reduces BAT-mediated adaptive thermogenesis, and causes obesity and insulin resistance. Brown adipose tissue (BAT) dissipates chemical energy in the form of heat as a defence against hypothermia and obesity. Current evidence indicates that brown adipocytes arise from Myf5+ dermotomal precursors through the action of PR domain containing protein 16 (PRDM16) transcriptional complex1,2. However, the enzymatic component of the molecular switch that determines lineage specification of brown adipocytes remains unknown. Here we show that euchromatic histone-lysine N-methyltransferase 1 (EHMT1) is an essential BAT-enriched lysine methyltransferase in the PRDM16 transcriptional complex and controls brown adipose cell fate. Loss of EHMT1 in brown adipocytes causes a severe loss of brown fat characteristics and induces muscle differentiation in vivo through demethylation of histone 3 lysine 9 (H3K9me2 and 3) of the muscle-selective gene promoters. Conversely, EHMT1 expression positively regulates the BAT-selective thermogenic program by stabilizing the PRDM16 protein. Notably, adipose-specific deletion of EHMT1 leads to a marked reduction of BAT-mediated adaptive thermogenesis, obesity and systemic insulin resistance. These data indicate that EHMT1 is an essential enzymatic switch that controls brown adipose cell fate and energy homeostasis.