Epigenomic regulation of adipogenesis and adipose expansion

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

I. We have investigated the roles of site-specific methyltransferases on histone H3K4, H3K9, H3K27, and H3K36 in regulation of adipogenesis and PPARgamma. We reported previously that H3K4me1/2 methyltransferases MLL3/MLL4 and associated PTIP control the induction of PPARgamma and C/EBPa and are essential for adipogenesis (Cho YW, Cell Metab 2009; Lee JE, eLife 2013; Jang Y, NAR 2019), that H3K9 methyltransferase G9a represses PPARgamma expression and adipogenesis (Wang L, EMBO J 2013), that H3K27 methyltransferase Ezh2 constitutively represses Wnt genes to facilitate adipogenesis (Wang L, PNAS 2010), and that depletion of Nsd2-mediated H3K36 methylation by histone H3.3 mutant H3.3K36M in progenitor cells impairs adipose tissue development and function (Zhuang L, Nat Comm 2018). We also showed that the epigenomic reader Brd4 controls cell identity gene induction and is essential for adipogenesis in vivo (Lee JE, Nat Comm 2017). Together, these findings indicate that epigenomic factors play critical roles in the regulation of adipogenesis (reviewed in Lee JE, MCB 2019). II. Using conditional knockout mice and preadipocytes, we found surprisingly that although ligand-bound glucocorticoid receptor (GR) accelerates adipogenesis in culture, endogenous GR is dispensable for adipogenesis in culture and in mice (Park Y, MCB 2017a). We also found that Transcription factors (TFs) KLF4 and Krox20 are dispensable for adipogenesis in culture and in mice (Park Y, 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 BAT. Our data provide a rich resource for understanding epigenomic regulation of brown adipogenesis in culture (Lai B, 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 (Lee JE, MCB 2020). V. In 2021, we reported 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 (Park Y, Nat Comm 2021). VI. MED1 often serves as a surrogate of the general transcription coactivator complex Mediator for identifying active enhancers. MED1 is required for phenotypic conversion of fibroblasts to adipocytes in vitro, but its role in adipose development and expansion in vivo has not been reported. Here, we show that MED1 is not generally required for transcription during adipogenesis in culture and that MED1 is dispensable for adipose tissue development in mice. Instead, MED1 is required for postnatal adipose expansion and the induction of fatty acid and triglyceride synthesis genes after pups switch diet from high-fat maternal milk to carbohydrate-based chow. During adipogenesis, MED1 is dispensable for induction of LDTFs PPAR and C/EBP but is required for lipid accumulation in the late phase of differentiation. Mechanistically, MED1 controls the induction of lipogenesis genes by facilitating lipogenic TF ChREBP- and SREBP1a-dependent recruitment of Mediator to active enhancers. Together, our findings identify a gene-specific regulatory role of MED1 as a lipogenesis coactivator required for postnatal adipose expansion (Jang Y, Genes Dev 2021).