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SUMMARY Brown adipose tissue harbors UCP1 to dissipate chemical energy as heat. However, the transcriptional network that governs the thermogenic gene program is incompletely understood. Zc3h10, a CCCH-type zinc finger protein, has recently been reported to bind RNA. However, we report here that Zc3h10 functions as a transcription factor to activate UCP1 not through the enhancer region, but by binding to a far upstream region of the UCP1 promoter. Upon sympathetic stimulation, Zc3h10 is phosphorylated at S126 by p38 mitogen-activated protein kinase (MAPK) to increase binding to the distal region of the UCP1 promoter. Zc3h10, as well as mutant Zc3h10, which cannot bind RNA, enhances thermogenic capacity and energy expenditure, protecting mice from diet-induced obesity. Conversely, Zc3h10 ablation in UCP1+ cells in mice impairs thermogenic capacity and lowers oxygen consumption, leading to weight gain. Hence, Zc3h10 plays a critical role in the thermogenic gene program and may present future targets for obesity therapeutics.

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.

13Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical 14 energy into heat, thereby increasing energy expenditure. Here, we identify Dot1L, the only 15 known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally 16 activates the UCP1 promoter and other BAT genes. Through a direct interaction, Dot1L is 17 recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator 18 by methylating H3K79. We also show that Dot1L is induced during brown fat cell differentiation 19 and by cold exposure and that Dot1L and its H3K79 methyltransferase activity is required for 20 thermogenic gene program. Furthermore, we demonstrate that Dot1L ablation in mice using 21 UCP1-Cre prevents activation of UCP1 and other target genes to reduce thermogenic capacity 22 and energy expenditure, promoting adiposity. Hence, Dot1L plays a critical role in the 23 thermogenic program and may present as a future target for obesity therapeutics. 24 25 42 UCP1 gene. A multitude of transcriptional regulators have been implicated in the transcription of 43 UCP1, including transcription factors, Zfp516, IRF4 and EBF2, and transcriptional coregulators,

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