Jmjd3-Mediated H3K27me3 Dynamics Orchestrate Brown Fat Development and Regulate White Fat Plasticity

Abstract

SUMMARY Progression from brown preadipocytes to adipocytes engages two transcriptional programs: the expression of adipogenic genes common to both brown fat (BAT) and white fat (WAT), and the expression of BAT-selective genes. However, the dynamics of chromatin states and epigenetic enzymes involved remain poorly understood. Here we show that BAT development is selectively marked and guided by repressive H3K27me3, and is executed by its demethylase Jmjd3. We find that a significant subset of BAT-selective genes, but not common fat genes or WAT-selective genes, are demarcated by H3K27me3 in both brown and white preadipocytes. Jmjd3-catalyzed removal of H3K27me3, in part through Rreb1-mediated recruitment, is required for expression of BAT-selective genes and for development of beige adipocytes both in vitro and in vivo. Moreover, gain- and loss-of-function Jmjd3 transgenic mice show age-dependent body weight reduction and cold intolerance, respectively. Together, we identify an epigenetic mechanism governing BAT fate determination and WAT plasticity.

Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis

“…Mass spectrometrybased analysis of the human proteome (Proteomics DB) has demonstrated that heart, pancreas, lymphocytes, and colon express RREB1 ( 38 ). The role of RREB1 in regulation of blood glucose and atherosclerosis is unknown, but interestingly, RREB1 was recently demonstrated to modify histones by aiding in removal of histone H3 lysine 27 trimethylation (H3K27me3) marks, which often characterize silenced regions, thereby promoting Ucp1 and Cidea expression in brown adipocytes ( 39 ). This mechanism of action of RREB1 was shown to be due to recruitment of Jmjd3, an H3K27me3 demethylase.…”

Cbx4 Sumoylates Prdm16 to Regulate Adipose Tissue Thermogenesis

“…A significant subset of BAT-selective genes, including key thermogenic transcriptional regulators such as Prdm16, Pparα, and Pgc1β, was marked by H3K27me3 at their promoter/enhancer regions in brown preadipocytes (Pan et al, 2015). We surmised that potential thermogenic regulators might possess a similar pattern of H3K27me3 modification and gene expression.…”

“…We surmised that potential thermogenic regulators might possess a similar pattern of H3K27me3 modification and gene expression. We therefore analyzed published chromatin immunoprecipitation sequencing (ChIP-seq) (GEO: GSE55469) and RNA sequencing (RNA-seq) (GEO: GSE56367) datasets (Pan et al, 2015), and we identified Cbx4 as a candidate. As shown in Figure 1A, Cbx4 promoter was modified by H3K27me3 in brown preadipcoytes, and this modification was largely removed in mature brown adipocytes.…”

“…We have previously shown that H3K27me3 modification deposited by PRC2 marks a significant subset of BAT-selective genes, including Prdm16 in preadipocytes (Pan et al, 2015). Interestingly, as a PRC1 subunit, Cbx4 is modified by H3K27me3 in preadipoytes as well.…”

“…We have previously shown that PRC2-catalyzed H3K27me3 modification prepares and safeguards a BAT-selective gene expression program in BAT development and browning of WAT (Pan et al, 2015). To date, it is unknown whether PRC1 or any of its subunits plays a role in adipose development and function.…”