Epigenomic Regulation of PPARgamma and Adipogenesis

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We have investigated the roles of site-specific methyltransferases on K4, K9, K27, K36 and K79 of histone H3 (H3K4, H3K9, H3K27, H3K36 and H3K79, respectively) in regulation of adipogenesis and PPARgamma. We reported previously that H3K4me1 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). 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 KLF4 and Krox20 are dispensable for adipogenesis in culture and in mice (Park Y, MCB 2017b). 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). Transcription factors (TFs) 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 However, the mechanism that controls the induction of C/EBPb and C/EBPd remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPARgamma and C/EBPa during adipogenesis. Here we show MLL3/MLL4/PTIP-associated protein PAGR1 (also known as PA1) 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. Deletion of Pagr1 in white and brown preadipocytes prevents the induction of C/EBPb and C/EBPd and leads to severe defects in adipogenesis. Adipogenesis defect in PAGR1-deficient cells can be rescued by ectopic expression of C/EBPb or PPARgamma. Finally, deletion of Pagr1 in Myf5+ precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBPb and C/EBPd, PAGR1 plays a critical role in adipogenesis(Lee JE, MCB 2020).