Enhancer epigenomic regulation in differentiation, development and cancer

Abstract

Enhancers control cell type‐specific gene expression and are marked by H3K4me1. Active enhancers are further marked by H3K27ac. We previously identified CBP/p300 as major H3K27 acetyltransferases and MLL3/MLL4 as major enhancer H3K4me1 methyltransferases [1, 2]. We show that during differentiation of adipocytes, myocytes and ES cells, MLL3/MLL4 are required for enhancer activation, cell type‐specific gene expression, and cell differentiation [2, 3]. Further, we show that while enhancer‐priming by MLL3/MLL4 is dispensable for cell identity maintenance, it controls cell fate transition by orchestrating CBP/p300‐mediated enhancer activation. MLL4 protein, rather than MLL4‐mediated H3K4me1, controls p300 recruitment to enhancers [3, 4].Our data suggest a model of sequential actions of epigenomic regulators on enhancers: 1) pioneer TFs and lineage‐determining TFs 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 Pol II to establish enhancer‐promoter interactions and activate cell type‐specific genes (Nat Comm, in press).MLL3/MLL4 are tumor suppressors frequently mutated in many types of cancers as well as developmental diseases. We show that MLL3/MLL4 are required for the development of adipose, muscle, mammary gland, B cells, T cells, and heart and that depletion of MLL3/MLL4 in mice promotes tumorigenesis [2, 5–9]. Our findings suggest that mutations in MLL3/MLL4 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 developmental diseases and cancers.Support or Funding InformationThis work was supported by the Intramural Research Program of the NIDDK, NIH.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.