Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis.
Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis.
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DOI：
10.1038/s41467-017-02403-5
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发表时间：
2017-12-20
影响因子：
16.6
通讯作者：
Ge K
中科院分区：
文献类型：
--
作者：
Lee JE;Park YK;Park S;Jang Y;Waring N;Dey A;Ozato K;Lai B;Peng W;Ge K
表观基因组阅读器Brd 4是癌症的重要药物靶标。然而，它在细胞分化和动物发育中的作用在很大程度上仍不清楚。使用两个条件性基因敲除小鼠品系和衍生细胞，我们证明，Brd 4控制细胞身份基因诱导，是必不可少的脂肪和肌生成。Brd 4在分化过程中与谱系决定转录因子（LDTF）共定位在活性增强子上。LDTF与H3 K4单甲基转移酶MLL 3/MLL 4（KMT 2C/KMT 2D）和H3 K27乙酰转移酶CBP/p300协调以将Brd 4募集到分化期间激活的增强子。Brd 4缺失阻止了增强子上介体和RNA聚合酶II转录机制的富集，但不阻止LDTF、MLL 3/MLL 4介导的H3 K4 me 1和CBP/p300介导的H3 K27 ac的富集。因此，Brd 4缺失阻止增强子RNA产生、细胞身份基因诱导和细胞分化。有趣的是，Brd 4是维持分化细胞中细胞身份基因的关键。这些发现将Brd 4鉴定为增强子表观基因组阅读器，其将活性增强子与分化中的细胞身份基因诱导联系起来。尽管是一个重要的癌症药物靶标，但表观遗传阅读器Brd 4在细胞分化和发育中的作用仍不清楚。在这里，作者提供的证据表明，Brd 4通过与活性增强子结合来调节基因表达，在脂肪形成和肌肉形成中起着重要作用。
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. Despite being an important cancer drug target, the role of epigenetic reader Brd4 in cell differentiation and development remains unclear. Here, the authors provide evidence that Brd4 plays an important role in adipogenesis and myogenesis by binding to active enhancers to regulate gene expression.
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影响因子：
30.8
作者：
He, Housheng Hansen;Meyer, Clifford A.;Shin, Hyunjin;Bailey, Shannon T.;Wei, Gang;Wang, Qianben;Zhang, Yong;Xu, Kexin;Ni, Min;Lupien, Mathieu;Mieczkowski, Piotr;Lieb, Jason D.;Zhao, Keji;Brown, Myles;Liu, X. Shirley
通讯作者：
Liu, X. Shirley
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
DOI：
10.1126/science.1249830
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baud MGJ;Lin-Shiao E;Cardote T;Tallant C;Pschibul A;Chan KH;Zengerle M;Garcia JR;Kwan TT;Ferguson FM;Ciulli A
通讯作者：
Ciulli A
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK