Epigenomic regulation of adipogenesis and obesity-associated adipose expansion

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

I. We have investigated the roles of histone H3K4, H3K9, H3K27 and H3K36 methyltransferases in regulation of adipogenesis and PPARgamma. We reported that H3K4me1 methyltransferases MLL3/MLL4 and associated PTIP control the induction of PPARgamma and C/EBPa and are essential for adipogenesis (Cell Metab 2009; eLife 2013; NAR 2019), that H3K9 methyltransferase G9a represses PPARgamma expression and adipogenesis (EMBO J 2013), that H3K27 methyltransferase Ezh2 constitutively represses Wnt genes to facilitate adipogenesis (PNAS 2010), and that depletion of Nsd2-mediated H3K36 methylation by histone H3.3 mutant H3.3K36M impairs adipose tissue development and function (Nat Comm 2018). We also showed that the epigenomic reader Brd4 controls cell identity gene induction and is essential for adipogenesis in vivo (Nat Comm 2017). Together, these findings indicate that epigenomic factors play critical roles in the regulation of adipogenesis (reviewed in MCB 2019). II. Using conditional knockout mice and preadipocytes, we found surprisingly that although glucocorticoid receptor (GR) accelerates adipogenesis in culture, endogenous GR is dispensable for adipogenesis in culture and in mice (MCB 2017a). We also corrected the literature and demonstrated that transcription factors (TFs) KLF4 and Krox20 are dispensable for adipogenesis in culture and in mice (MCB 2017b). III. We profiled genomic binding of enhancer epigenomic writers (MLL4, CBP), adipogenic TFs (EBF2, C/EBPa, C/EBPb, PPARgamma), coactivator MED1, RNA Polymerase II, as well as epigenome (H3K4me1/2/3, H3K9me2, H3K27me3, H3K36me3, H3K27ac), transcriptome, and chromatin opening during adipogenesis of immortalized preadipocytes derived from mouse brown adipose tissue. Our data provide a rich resource for understanding epigenomic regulation of brown adipogenesis in culture (NAR 2017). IV. C/EBPb and C/EBPd are induced within hours after initiation of adipogenesis in culture. They directly promote expression of master adipogenic TFs PPARgamma and C/EBPa and are required for adipogenesis in vivo. We reported that MLL3/MLL4/PTIP-associated protein PAGR1 cooperates with phosphorylated CREB and ligand-activated GR to directly control the induction of C/EBPb and C/EBPd in the early phase of adipogenesis (MCB 2020). V. We found that BAF is the SWI/SNF chromatin remodeling complex that colocalizes with MLL4 and lineage-determining TFs (LDTFs) on active enhancers. BAF is required for adipogenesis while the promoter enriched SWI/SNF complex PBAF is dispensable (Nat Comm 2021). VI. We identified a gene-specific regulatory role of MED1 as a lipogenesis coactivator required for postnatal adipose expansion (Genes Dev 2021). VII. We have found that in mice, deletion of enzymatic subunits of the chromatin remodeling complex ISWI in lineage-specific precursor cells impairs adipose and muscle development. In culture, KO of ISWI enzymatic subunits does not affect cell growth but leads to severe defects in adipogenesis and myogenesis. VIII. We are using knockout and knockin mice for H3K4 methyltransferases MLL1 and MLL2 to investigate their roles in adipose tissue development and expansion.