Critical Role of Histone Deacetylase 3 for Acute Adaptive Thermogenesis in Brown Adipose Tissue

May 1, 2017, 2PM

302- 309

Abstract:

Brown adipose tissue (BAT) is a thermogenic organ that protects animals against hypothermia via non-shivering thermogenesis mediated by UCP1-dependent respiration. However, the transcriptional mechanisms that determine BAT thermogenic capacity are unknown. Histone deacetylase 3 (HDAC3) is ubiquitously expressed epigenomic modulator that regulates histone and non-histone target deacetylation. Although HDAC3 canonically acts as a corepressor, mice with BAT-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure with nearly absent UCP1 and dramatic transcriptional silence of Ucp1 gene and upstream enhancers in BAT. By genomewide analysis of stead-state mRNA, various cistrome data, and nascent transcriptions at genes and enhancers, we show that HDAC3 functions as a coactivator for ERRa mediated by deacetylation of PGC1-a. Importantly, HDAC3 is required for the basal transcription of Ucp1, Pgc1-a, and OXPHOS genes. Thus HDAC3 uniquely pri mes UCP1-depenent thermogenic transcriptional program in BAT to maintain critical capacity for thermogenesis that can be engaged upon acute cold challenge..