Brd4 controls cell identity gene induction during differentiation

Authors

• J Lee
• W Peng
• K Ge

Abstract

Enhancers are critical for cell-type-specific gene expression, cell differentiation and animal development. There are two major types of enhancers in mammalian cells, primed and active, which are marked by distinct histone modification patterns. Primed enhancers are marked by H3K4 mono- and di-methylations (H3K4me1/2) while active enhancers are further marked by H3K27 acetylation (H3K27ac). MLL3/MLL4 and CBP/p300 are major enhancer H3K4me1/2 methyltransferases and H3K27 acetyltransferases, respectively. We previously showed that MLL3/MLL4-mediated enhancer priming is required for CBP/p300-mediated enhancer activation during cell differentiation. In this study, we sought to understand the mechanism that links enhancer activation with gene induction. Using adipogenesis as a model system, we show that the epigenomic reader Brd4 exhibits cell-type- and differentiation-stage-specific genomic binding and co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Lineage-determining TFs and enhancer epigenomic writers MLL3/MLL4 and CBP/p300 coordinate to recruit Brd4 to active enhancers during adipogenesis. Deletion of Brd4 does not affect the binding of the pioneer adipogenic TF C/EBPβ and the enrichment of H3K4me1 and H3K27ac on active enhancers during adipogenesis. However, the loss of Brd4 prevents the binding of transcription coactivator Mediator and RNA Polymerase II on active enhancers. As a consequence, Brd4 is required for enhancer RNA (eRNA) production, cell identity gene induction, and cell differentiation. Together, these findings identify Brd4 as an enhancer epigenomic reader that links enhancer activation and cell-type-specific gene expression during differentiation.

Scientific Focus Area: Chromosome Biology

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