Brd4 binds to active enhancers to control cell identity gene induction during differentiation

Authors

• J Lee
• Y Park
• K Ge

Abstract

The epigenomic reader Brd4 is an important drug target for cancers and inflammatory diseases. However, it’s role in cell differentiation and animal development remains largely unclear. Using conditional knockout mice and cells, we show Brd4 controls cell identity gene induction and is essential for adipogenesis and myogenesis. Brd4 exhibits cell-type- and differentiation-stage-specific genomic binding and co-localizes with lineage-determining transcription factors (LDTFs) on active enhancers during differentiation. LDTFs coordinate with histone H3K4 mono-methyltransferases MLL3/MLL4 and H3K27 acetyltransferases CBP/p300 to recruit Brd4 to enhancers activated during differentiation. Deletion of Brd4 does not affect the binding of LDTFs and the enrichment of MLL3/MLL4-mediated H3K4me1 and CBP/p300-mediated H3K27ac on enhancers, but prevents the enhancer-binding of Mediator and RNA Polymerase II. Consequently, Brd4 deletion prevents enhancer RNA production, cell identity gene induction, and cell differentiation. These findings identify Brd4 as an enhancer epigenomic reader that links active enhancers with cell identity gene induction during differentiation.

Scientific Focus Area: Chromosome Biology

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