Histone Deacetylase 3 Prepares Brown Adipose Tissue For Acute Thermogenic Challenge [ChIP-Seq, GRO-Seq]. Mus musculus

Brown adipose tissue (BAT) is a thermogenic organ that requires Uncoupling Protein 1 (UCP1) to dissipate chemical energy as heat, to defend core body temperature against hypothermia, and counteract obesity and metabolic diseases1. However, the transcriptional mechanism ensuring BAT thermogenic capacity for survival prior to environmental cold is unknown. Here we show histone deacetylase 3 (HDAC3) is a required transcriptional regulator of BAT enhancers to ensure thermogenic aptitude and survival. Mice with genetic ablation of HDAC3 become severely hypothermic and fail to survive acute cold exposure. UCP1 is nearly absent in BAT lacking HDAC3 and there is marked down-regulation of mitochondrial oxidative phosphorylation (OXPHOS) genes. Remarkably, although HDAC3 canonically functions as a transcriptional corepressor2, HDAC3 functions as a coactivator of the estrogen-related receptor _ (ERR_) in BAT, and loss of HDAC3 leads to robust global down-regulation of ERR±-driven enhancers. HDAC3 coactivation of ERR_ is mediated through deacetylation of PGC-1_ and is required for basal transcription of Ucp1, OXPHOS, and Pgc-1_. Thus, HDAC3 uniquely primes Ucp1 and thermogenic gene transcription to ensure immediate BAT-driven thermogenesis upon acute exposure to dangerously cold temperatures. Overall design: Interscapular BAT from wild-type and HDAC3 KO animals of C57BL/6 background were adapted to 22C or 29C (thermoneutrality) for ChIP-seq and GRO-seq studies. ChIP-seq studies of HDAC3, ERR- alpha, NCoR, and H3K27ac were performed from individual mice of each genotype and immunoprecipitations were subsequently pooled for sequencing. Nascent transcription changes and eRNAs were measured in WT and HDAC3 KO mice by GRO-seq through pooling 10 interscapular BAT pads from individual mice for nuclei isolation and subsequent nuclear-run on reactions and GRO-seq library construction.