Transcriptional enhancers control cell-type-specific gene expression. Of the two major types of enhancers in mammalian cells, primed enhancers are marked by histone H3K4 mono-methylation (H3K4me1) while active enhancers are further marked by H3K27 acetylation (H3K27ac). We identified MLL3 (KMT2C)/MLL4 (KMT2D) as the major H3K4 mono-methyltransferases and CBP/p300 as the major H3K27 acetyltransferases in mammalian cells (Jin Q, EMBO J 2011; Lee J, eLife 2013). In search for novel coactivators for the master adipogenic transcription factor (TF) PPAR, we identified a nuclear protein complex that contains H3K4me1 methyltransferases MLL3/MLL4, 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). Using adipogenesis and myogenesis as models, we showed that H3K4me1 methyltransferases MLL3/MLL4 co-localize with lineage-determining TFs on active enhancers. MLL3/MLL4 are required for enhancer activation, cell-type-specific gene induction, and cell differentiation (Lee J, eLife 2013). Using tissue-specific knockout mice, we showed that MLL3/MLL4 are essential for the development of various tissues including adipose, 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 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 in differentiation and 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. More recently, using 2 conditional knockout mouse strains and derived cells, we investigated the role of the epigenomic reader Brd4 in differentiation and development. We show that Brd4 co-localizes with lineage-determining TFs (LDTFs) on active enhancers during cell differentiation. Brd4 controls cell identity gene induction and is essential for adipogenesis and myogenesis. These findings identify Brd4 as an enhancer epigenomic reader that links active enhancers with cell identity gene induction in differentiation (Lee J, Nat Commun 2017). Together, our data suggest a model of sequential actions of epigenomic regulators on enhancers: 1) pioneer TFs and LDTFs recruit MLL3/MLL4 to prime enhancer regions and label them with H3K4me1; 2) MLL3/MLL4 facilitate the binding of CBP/p300, which activate enhancers and label them with H3K27ac; 3) H3K27ac and acetylated TFs are recognized by the epigenomic reader Brd4, which recruits Mediator and RNA Polymerase II to establish enhancer-promoter interactions and activate cell type-specific gene expression (Lee J, Nat Commun 2017).
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