RNA 与多梳抑制复合物 2 之间的调控相互作用。
Regulatory interactions between RNA and polycomb repressive complex 2.
机构信息
Howard Hughes Medical Institute, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Mol Cell. 2014 Jul 17;55(2):171-85. doi: 10.1016/j.molcel.2014.05.009. Epub 2014 May 29.
Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that is localized to thousands of mammalian genes. Though important to human disease and as a drug target, how PRC2 is recruited remains unclear. One model invokes cis-regulatory RNA. Herein, we biochemically and functionally probe PRC2's recognition of RNA using the X-inactivation model. We observe surprisingly high discriminatory capabilities. While SUZ12 and JARID2 subunits can bind RNA, EZH2 has highest affinity and is somewhat promiscuous. EED regulates the affinity of EZH2 for RNA, lending greater specificity to PRC2-RNA interactions. Intriguingly, while RNA is crucial for targeting, RNA inhibits EZH2's catalytic activity. JARID2 weakens PRC2's binding to RNA and relieves catalytic inhibition. We propose that RNA guides PRC2 to its target but inhibits its enzymatic activity until PRC2 associates with JARID2 on chromatin. Our study provides a molecular view of regulatory interactions between RNA and PRC2 at the chromatin interface.
多梳抑制复合物 2（PRC2）是一种组蛋白甲基转移酶，定位于数千个哺乳动物基因上。尽管它对人类疾病和药物靶点很重要，但 PRC2 的募集方式仍不清楚。一种模型涉及顺式调控 RNA。在此，我们使用 X 染色体失活模型从生化和功能上探测 PRC2 对 RNA 的识别。我们观察到令人惊讶的高区分能力。虽然 SUZ12 和 JARID2 亚基可以结合 RNA，但 EZH2 具有最高的亲和力且有些混杂。EED 调节 EZH2 对 RNA 的亲和力，使 PRC2-RNA 相互作用更具特异性。有趣的是，虽然 RNA 对于靶向至关重要，但 RNA 抑制了 EZH2 的催化活性。JARID2 削弱了 PRC2 与 RNA 的结合，并解除了催化抑制。我们提出，RNA 引导 PRC2 到达其靶标，但抑制其酶活性，直到 PRC2 在染色质上与 JARID2 结合。我们的研究提供了在染色质界面上 RNA 和 PRC2 之间的调控相互作用的分子视角。
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