We use adipogenesis as the major model system to study epigenomic regulation of cell differentiation and cell fate transition, with a focus on transcriptional enhancers. The master regulator of adipogenesis, PPARgamma, is a nuclear receptor and thus a ligand-activated transcription factor (TF). In search for novel cofactors for PPAR, we previously identified a nuclear protein complex that contains H3K4 methyltransferase MLL3 (KMT2C) or MLL4 (KMT2D), H3K27 demethylase UTX (KDM6A), PTIP, PA1, NCOA6, and the WRAD subcomplex consisting of WDR5, RbBP5, Ash2L and DPY30 (Cho YW, JBC 2007; Hong S, PNAS 2007). We showed that PTIP is required for PPARgamma and C/EBPalpha expression and adipogenesis (Cho YW, Cell Metab 2009). Using adipogenesis and myogenesis as model systems, we found that MLL3 and MLL4 are major enhancer H3K4me1/2 methyltransferases and are essential for enhancer activation, cell-type-specific gene induction and cell differentiation (Lee J, eLife 2013). We showed that MLL3 and MLL4 are essential for the development of adipose tissue, muscle, mammary gland, B cells, T cells, and heart (summarized in Froimchuk E, Gene 2017). Using adipogenesis, ES cell differentiation and somatic cell reprogramming as model systems, we found that although enhancer priming by MLL3/MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating H3K27 acetyltransferases CBP/p300-mediated enhancer activation (Wang C, PNAS 2016; Lai B, Nucleic Acids Res 2017). We also found that UTX protein, but not its H3K27 demethylase activity, is required for ES cell differentiation and mouse development (Wang C, PNAS 2012; Yoo KH, MCB 2016; Faralli H, JCI 2016). Our data suggest that UTX functions through MLL3/MLL4 to regulate enhancer activation during ES cell differentiation and animal development. Interestingly, UTX demethylase activity is required for satellite cell-mediated muscle regeneration (Faralli H, JCI 2016). MLL3/MLL4 and UTX are frequently mutated in multiple types of cancers and developmental diseases (Froimchuk E, Gene 2017). Our findings suggest that mutations in MLL3/MLL4 and UTX would lead to defects in enhancer activation, cell-type-specific gene expression and cell differentiation. Such a mechanism may contribute to the pathogenesis of these cancers and developmental diseases. We are currently investigating how epigenomic writers MLL3/MLL4 and CBP/p300 and the epigenomic reader Brd4 regulate enhancer activation and enhancer-promoter interaction.
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