PT  - JOURNAL ARTICLE
AU  - Danielle Yi
AU  - Hai P. Nguyen
AU  - Jennie Dinh
AU  - Jose A. Viscarra
AU  - Ying Xie
AU  - Jon M. Dempersmier
AU  - Yuhui Wang
AU  - Hei Sook Sul
TI  - Dot1L interacts with Zc3h10 to activate UCP1 and other thermogenic genes
AID  - 10.1101/2020.06.22.154963
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.22.154963
4099  - http://biorxiv.org/content/early/2020/07/14/2020.06.22.154963.short
4100  - http://biorxiv.org/content/early/2020/07/14/2020.06.22.154963.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.