Enhancer for UCP1 transcription and thermogenesis

Obesity, the accumulation of excess white adipose tissue (WAT), has become an epidemic and is associated with chronic metabolic diseases, such as type 2 diabetes. While WAT serves primarily as an energy storage organ, brown adipose tissue (BAT) dissipates energy by generating heat mainly via UCP1 for maintenance of body temperature. Increasing BAT activity by activating UCP1 may promote energy expenditure to combat obesity. We have been studying transcriptional activation of UCP1 and thermogenic gene program and previously found two transcription factors, Zfp516 and Zc3h10 and recruitment of their coregulators PRDM16/LSD1 and Dot1L, respectively, critical for activation of UCP1 and thermogenic program. In continuing our efforts to understand UCP1 transcription, our recent ATAC-seq and 3C-based crosslinking identified a potential new enhancer far upstream of UCP1 locus. We will study this region to act as an enhancer by examining histone modification, UCP1 promoter activation, and eRNA production, as well as in the genomic context by CRISPRa and CRISPRi. Moreover, we will examine the involvement of an associated transcription factor for its enhancer function. Finally, we will assess the impact of this enhancer and the transcription factor on thermogenesis, adiposity, and glucose/insulin homeostasis in vivo in mice. Overall, elucidating the role of a previously uncharacterized far upstream UCP1 enhancer and the associated factor will help us to fully understand UCP1 transcription and thus thermogenesis. Our studies may provide new obesity/diabetes therapeutics in the future. 1