Novel transcriptional regulators for thermogenic program

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Obesity, the accumulation of excess white adipose tissue (WAT), is associated with type 2 diabetes and other chronic diseases and has become an epidemic. While WAT is primarily an energy storage organ, brown adipose tissue (BAT) dissipates energy for heat generation via UCP1 to maintain body temperature. With the recognition of BAT/BAT-like tissues in human adults, increasing BAT or BAT activity may combat obesity. By screening a library of known and putative transcription factors that can activate UCP1 promoter, we recently have identified a largely uncharacterized a protein belonging to C3H zinc finger family, that can robustly activate UCP1 and other thermogenic genes. This transcription factor is enriched in BAT versus WAT and is induced upon cold-exposure. We detected binding of this C3H factor at the promoter regions of UCP1 and other BAT genes by EMSA and SELEX as well as by ChIP. Ablation by CRISPR-Cas9 system in BAT cells in culture suppressed UCP1 and other target genes to reduce uncoupled respiration. Moreover, overexpression in adipose tissue in mice increased energy expenditure to accompany resistance to diet- induced obesity, whereas ablation in adipose tissue promoted obesity and insulin resistance. To further examine the function of this factor, by TAP-Mass spec analysis, we identified a histone methyltransferase, which we found to interact and function synergistically. Adipose specific ablation of this epigenetic factor in mice also decreased energy expenditure promoting obesity. Our goal is to understand the molecular mechanisms and physiological significance of this new C3H transcription factor and its interacting protein for the thermogenic gene program and thermogenesis: Aim 1 is to investigate the function of this C3H factor in activating UCP1 promoter and study its genome-wide targets. Aim 2 is to examine the relationship and function of its interacting cofactor in epigenetic regulation of the thermogenic gene program. Finally, Aim 3 is to study the in vivo role of this C3H factor, its cofactor and their relationship in thermogenesis and adiposity by gain- and loss-of function studies in mice. Our research will help better understand the thermogenic program and may provide targets for developing effective obesity therapeutics in the future.