Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes.
Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes.
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作者：
Yi D;Nguyen HP;Dinh J;Viscarra JA;Xie Y;Lin F;Zhu M;Dempersmier JM;Wang Y;Sul HS
棕色脂肪组织是一种代谢有益的器官，能够将化学能耗散成热量，从而增加能量消耗。在这里，我们确定Dot 1 l，唯一已知的H3 K79甲基转移酶，作为Zc 3 h10的转录激活Ucp 1启动子和其他BAT基因的相互作用的合作伙伴。通过直接相互作用，Dot 1 l被Zc 3 h10募集到产热基因的启动子区域，通过甲基化H3 K79作为共激活因子发挥作用。我们还表明，Dot 1 l诱导棕色脂肪细胞分化和冷暴露和Dot 1 l和它的H3 K79甲基转移酶活性所需的产热基因程序。此外，我们证明了使用Ucp 1-Cre在小鼠中进行Dot 1 l消融可以防止Ucp 1和其他靶基因的激活，从而降低产热能力和能量消耗，促进肥胖。因此，Dot 1 l在产热程序中起着关键作用，并可能成为肥胖治疗的未来靶点。
Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.