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

Author

Listed:
  • Ji-Eun Lee

    (National Institutes of Health)

  • Young-Kwon Park

    (National Institutes of Health)

  • Sarah Park

    (National Institutes of Health)

  • Younghoon Jang

    (National Institutes of Health)

  • Nicholas Waring

    (National Institutes of Health
    The George Washington University)

  • Anup Dey

    (National Institutes of Health)

  • Keiko Ozato

    (National Institutes of Health)

  • Binbin Lai

    (National Institutes of Health
    The George Washington University)

  • Weiqun Peng

    (The George Washington University)

  • Kai Ge

    (National Institutes of Health)

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.

Suggested Citation

  • Ji-Eun Lee & Young-Kwon Park & Sarah Park & Younghoon Jang & Nicholas Waring & Anup Dey & Keiko Ozato & Binbin Lai & Weiqun Peng & Kai Ge, 2017. "Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02403-5
    DOI: 10.1038/s41467-017-02403-5
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    Cited by:

    1. Jiahui Du & Yili Liu & Jinrui Sun & Enhui Yao & Jingyi Xu & Xiaolin Wu & Ling Xu & Mingliang Zhou & Guangzheng Yang & Xinquan Jiang, 2024. "ARID1A safeguards the canalization of the cell fate decision during osteoclastogenesis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Marie Bobowski-Gerard & Clémence Boulet & Francesco P. Zummo & Julie Dubois-Chevalier & Céline Gheeraert & Mohamed Bou Saleh & Jean-Marc Strub & Amaury Farce & Maheul Ploton & Loïc Guille & Jimmy Vand, 2022. "Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Annkatrin Bressin & Olga Jasnovidova & Mirjam Arnold & Elisabeth Altendorfer & Filip Trajkovski & Thomas A. Kratz & Joanna E. Handzlik & Denes Hnisz & Andreas Mayer, 2023. "High-sensitive nascent transcript sequencing reveals BRD4-specific control of widespread enhancer and target gene transcription," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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