Enhancer regulation by H3K4 methyltransferase MLL4/KMT2D and associated factors

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

PPARgamma is a lineage-determining transcription factor (LDTF) essential for adipogenesis. In search for novel PPARgamma cofactors, we identified a nuclear protein complex that contains MLL3/4 and the H3K27 demethylase UTX (KDM6A) (JBC 2007, PNAS 2007). MLL3/4 and UTX are highly mutated in many types of cancers as well as Kabuki syndrome and congenital heart disease. We have shown: 1) MLL3/4 colocalize with LDTFs on active enhancers and are generally required for enhancer activation, cell-type-specific gene expression, cell differentiation, tissue development and tumor suppression (eLife 2013, Development 2016, NAR 2019, Development 2020, Nat Cell Biol 2023, reviewed in Gene 2017, MCB 2020a). MLL3/4 control cell fate transition by orchestrating H3K27 acetyltransferases CBP/p300-mediated enhancer activation (PNAS 2016, NAR 2017). 2) MLL3/4 proteins, rather than H3K4me1, controls p300 recruitment to enhancers during ES cell differentiation (PNAS 2016). Consistently, MLL3/4 enzymatic activities and H3K4me1 are largely dispensable for enhancer activation during ES cell differentiation. By inactivating MLL3/4 enzymatic activities in mice and ES cells, we show that MLL3/4 methyltransferase activities are redundant and are essential for early embryonic development. MLL3/4 enzymatic activities control early embryonic development and ES cell differentiation in a lineage-selective manner (Nat Genet 2023). 3) The epigenomic reader Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis. Our data suggest a model of sequential actions of epigenomic regulators on enhancers: i) LDTFs recruit MLL3/4 to prime enhancers, ii) MLL3/4 facilitate the binding of CBP/p300, which activate enhancers, iii) Brd4 recognizes active enhancers and recruits Mediator and RNA Polymerase II to activate cell-type-specific gene expression (Nat Commun 2017). 4) Positive feedback between MLL4 and the SWI/SNF chromatin remodeling complex BAF in promoting LDTF-dependent activation of cell type-specific enhancers (Nat Commun 2021). 5) UTX protein, but not its H3K27 demethylase activity, is required for ES cell differentiation and mouse development (PNAS 2012). Interestingly, UTX demethylase activity is required for stem cell-mediated muscle regeneration (JCI 2016). 6) While the MED1 subunit of the Mediator coactivator complex marks active enhancers, it plays a cell- and gene-specific regulatory role and is not generally required for transcription (Genes Dev 2021).