Zc3h10 Acts as a Transcription Factor and Is Phosphorylated to Activate the Thermogenic Program

Abstract

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. : Zc3h10 is a RNA-binding protein. Here, Yi et al. report Zc3h10 is a transcription factor that activates UCP1 and other BAT genes. Cold/β3 stimulation causes phosphorylation of Zc3h10 at S126 by p38 MAPK to increase its binding to targets genes and, thus, promotes thermogenic capacity and energy expenditure. Keywords: Zc3h10, RNA binding, phosphorylation, thermogenesis, UCP1, brown fat, brown adipose tissue, transcription factor