Dismissal of RNA Polymerase II Underlies a Large Ligand-Induced Enhancer Decommissioning Program.
Dismissal of RNA Polymerase II Underlies a Large Ligand-Induced Enhancer Decommissioning Program.
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RNA 聚合酶 II 的废弃是大规模配体诱导增强剂退役计划的基础。
DOI：
10.1016/j.molcel.2018.07.039
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发表时间：
2018
期刊：
影响因子：
16
通讯作者：
Rosenfeld,MichaelG
中科院分区：
文献类型：
--
作者：
Tan,Yuliang;Jin,Chunyu;Ma,Wubin;Hu,Yiren;Tanasa,Bogdan;Oh,Soohwan;Gamliel,Amir;Ma,Qi;Yao,Lu;Zhang,Jie;Ohgi,Kenny;Liu,Wen;Aggarwal,AneelK;Rosenfeld,MichaelG
核受体诱导转录激活和抑制程序负责发展，稳态和疾病。在这里，我们报告了一个以前被忽视的增强子退役策略的基础上大雌激素受体α（ERα）依赖性转录抑制计划。这种E2诱导程序的意外特征在于ERα间接募集到大量缺乏同源ERα DNA结合元件的先锋因子基础活性FOXA 1结合增强子。令人惊讶的是，这些基本活性的雌激素抑制（BAER）增强子被ERα依赖性的组蛋白去甲基化酶KDM 2A募集所解除，其功能独立于其去甲基化酶活性。相反，KDM 2A将E3泛素-蛋白连接酶NEDD 4拴在一起，使Pol II泛素化/消除，从而消除eRNA转录，随之而来的是靶基因下调。因此，我们的数据表明，Pol II泛素化/解雇可能作为一个潜在的广泛的战略利用间接结合的核受体废除大程序的先锋因子介导的，eRNA产生增强子。
Nuclear receptors induce both transcriptional activation and repression programs responsible for development, homeostasis, and disease. Here, we report a previously overlooked enhancer decommissioning strategy underlying a large estrogen receptor alpha (ERα)-dependent transcriptional repression program. The unexpected signature for this E2-induced program resides in indirect recruitment of ERα to a large cohort of pioneer factor basally active FOXA1-bound enhancers that lack cognate ERα DNA-binding elements. Surprisingly, these basally active estrogen-repressed (BAER) enhancers are decommissioned by ERα-dependent recruitment of the histone demethylase KDM2A, functioning independently of its demethylase activity. Rather, KDM2A tethers the E3 ubiquitin-protein ligase NEDD4 to ubiquitylate/dismiss Pol II to abrogate eRNA transcription, with consequent target gene downregulation. Thus, our data reveal that Pol II ubiquitylation/dismissal may serve as a potentially broad strategy utilized by indirectly bound nuclear receptors to abrogate large programs of pioneer factor-mediated, eRNA-producing enhancers.
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