JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex.
JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex.
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DOI：
10.1016/j.molcel.2018.03.006
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发表时间：
2018-04-19
期刊：
影响因子：
16
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Gao WW;Xiao RQ;Zhang WJ;Hu YR;Peng BL;Li WJ;He YH;Shen HF;Ding JC;Huang QX;Ye TY;Li Y;Liu ZY;Ding R;Rosenfeld MG;Liu W
虽然增强子在基因转录调控中的作用已经得到了很好的证实，但JmjC结构域蛋白在介导增强子激活中的作用仍然知之甚少。在这里，我们报道了含有JmjC结构域的蛋白6 （JMJD6）向雌激素受体α (ERα)结合的活性增强子募集是RNA聚合酶II募集和增强子RNA在增强子上产生所必需的，导致同源雌激素靶基因的转录暂停释放。JMJD6被发现在介质复合体中与MED12相互作用以调节其募集。出乎意料的是，JMJD6是MED12与CARM1相互作用所必需的，CARM1使MED12在多个精氨酸位点甲基化并调节其染色质结合。与其在转录激活中的作用一致，JMJD6是雌激素/ er α-诱导的乳腺癌细胞生长和肿瘤发生所必需的。我们的数据发现了雌激素/ er α-诱导增强子、编码基因激活和乳腺癌细胞效力的关键调节因子，为er阳性乳腺癌提供了潜在的治疗靶点。
Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC domain-containing proteins in mediating enhancer activation remain poorly understood. Here we report that recruitment of the JmjC domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 was found to interact with MED12 in the mediator complex to regulate its recruitment. Unexpectedly, JMJD6 is necessary for MED12 to interact with CARM1, which methylates MED12 at multiple arginine sites and regulates its chromatin binding. Consistent with its role in transcriptional activation, JMJD6 is required for estrogen/ERα-induced breast cancer cell growth and tumorigenesis. Our data have uncovered a critical regulator of estrogen/ERα-induced enhancer, coding gene activation and breast cancer cell potency, providing a potential therapeutic target of ER-positive breast cancers.
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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
影响因子：
4.6
作者：
Chen CF;Feng X;Liao HY;Jin WJ;Zhang J;Wang Y;Gong LL;Liu JJ;Yuan XH;Zhao BB;Zhang D;Chen GF;Wan Y;Guo J;Yan HP;He YW
通讯作者：
He YW
影响因子：
64.5
作者：
Hah N;Danko CG;Core L;Waterfall JJ;Siepel A;Lis JT;Kraus WL
通讯作者：
Kraus WL
DOI：
10.1073/pnas.1324151111
发表时间：
2014-05-20
影响因子：
11.1
作者：
Hsieh, Chen-Lin;Fei, Teng;Kantoff, Philip W.
通讯作者：
Kantoff, Philip W.
影响因子：
30.8
作者：
Carroll, Jason S.;Meyer, Clifford A.;Brown, Myles
通讯作者：
Brown, Myles