Brd4 结合到活性增强子上，以控制脂肪生成和肌生成过程中细胞身份基因的诱导。
Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis.
机构信息
Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Departments of Physics and Anatomy and Regenerative Biology, The George Washington University, Washington, DC, 20052, USA.
出版信息
Nat Commun. 2017 Dec 20;8(1):2217. doi: 10.1038/s41467-017-02403-5.
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.
表观基因组阅读器 Brd4 是癌症的一个重要药物靶点。然而，其在细胞分化和动物发育中的作用在很大程度上仍不清楚。使用两种条件性敲除小鼠品系和衍生细胞，我们证明 Brd4 控制细胞身份基因的诱导，并且对于脂肪生成和肌生成是必需的。在分化过程中，Brd4 与谱系决定转录因子（LDTFs）在活性增强子上共定位。LDTFs 与 H3K4 单甲基转移酶 MLL3/MLL4（KMT2C/KMT2D）和 H3K27 乙酰转移酶 CBP/p300 协调，将 Brd4 募集到分化过程中激活的增强子上。Brd4 的缺失阻止了中介体和 RNA 聚合酶 II 转录机制的富集，但不阻止 LDTFs、MLL3/MLL4 介导的 H3K4me1 和 CBP/p300 介导的 H3K27ac 的富集，在增强子上。因此，Brd4 的缺失阻止了增强子 RNA 的产生、细胞身份基因的诱导和细胞分化。有趣的是，Brd4 在分化细胞中维持细胞身份基因是可有可无的。这些发现确定了 Brd4 作为一个增强子表观基因组阅读器，它将活性增强子与分化过程中的细胞身份基因诱导联系起来。
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