Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis.

Abstract

The epigenomic reader Brd4 is an important drug target for cancers. However, its role in cell differentiation and animal development remains largely unclear. Using two conditional knockout mouse strains and derived cells, we demonstrate that Brd4 controls cell identity gene induction and is essential for adipogenesis and myogenesis. Brd4 co-localizes with lineage-determining transcription factors (LDTFs) on active enhancers during differentiation. LDTFs coordinate with H3K4 mono-methyltransferases MLL3/MLL4 (KMT2C/KMT2D) and H3K27 acetyltransferases CBP/p300 to recruit Brd4 to enhancers activated during differentiation. Brd4 deletion prevents the enrichment of Mediator and RNA polymerase II transcription machinery, but not that of LDTFs, MLL3/MLL4-mediated H3K4me1, and CBP/p300-mediated H3K27ac, on enhancers. Consequently, Brd4 deletion prevents enhancer RNA production, cell identity gene induction and cell differentiation. Interestingly, Brd4 is dispensable for maintaining cell identity genes in differentiated cells. These findings identify Brd4 as an enhancer epigenomic reader that links active enhancers with cell identity gene induction in differentiation.

• Authors: Ji-Eun Lee, Young-Kwon Park, Sarah Park, Younghoon Jang, Nicholas Waring, Anup Dey, Keiko Ozato, Binbin Lai, Weiqun Peng, Kai Ge
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 2217 (Dec 20 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29263365 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Brd4 protein, mouse
• Nuclear Proteins
• Transcription Factors
• Histone-Lysine N-Methyltransferase
• MLL3 protein, mouse
• MLL4 protein, mouse
• p300-CBP Transcription Factors
• RNA Polymerase II

Topics

• Adipogenesis (genetics)
• Animals
• Cell Differentiation (genetics)
• Cell Lineage
• Enhancer Elements, Genetic
• Epigenesis, Genetic
• Gene Expression Regulation
• Histone Code
• Histone-Lysine N-Methyltransferase (metabolism)
• Mice
• Mice, Knockout
• Muscle Development (genetics)
• Nuclear Proteins (genetics, metabolism)
• RNA Polymerase II (metabolism)
• Transcription Factors (genetics, metabolism)
• p300-CBP Transcription Factors (metabolism)