Portnoy Victoria, Lin Szu Hua Sharon, Li Kathy H, Burlingame Alma, Hu Zheng-Hui, Li Hao, Li Long-Cheng
Department of Urology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
Cell Res. 2016 Mar;26(3):320-35. doi: 10.1038/cr.2016.22. Epub 2016 Feb 23.
Small activating RNAs (saRNAs) targeting specific promoter regions are able to stimulate gene expression at the transcriptional level, a phenomenon known as RNA activation (RNAa). It is known that RNAa depends on Ago2 and is associated with epigenetic changes at the target promoters. However, the precise molecular mechanism of RNAa remains elusive. Using human CDKN1A (p21) as a model gene, we characterized the molecular nature of RNAa. We show that saRNAs guide Ago2 to and associate with target promoters. saRNA-loaded Ago2 facilitates the assembly of an RNA-induced transcriptional activation (RITA) complex, which, in addition to saRNA-Ago2 complex, includes RHA and CTR9, the latter being a component of the PAF1 complex. RITA interacts with RNA polymerase II to stimulate transcription initiation and productive elongation, accompanied by monoubiquitination of histone 2B. Our results establish the existence of a cellular RNA-guided genome-targeting and transcriptional activation mechanism and provide important new mechanistic insights into the RNAa process.
靶向特定启动子区域的小激活RNA（saRNAs）能够在转录水平刺激基因表达，这一现象被称为RNA激活（RNAa）。已知RNAa依赖于Ago2，并与靶启动子处的表观遗传变化相关。然而，RNAa的确切分子机制仍然难以捉摸。我们以人类CDKN1A（p21）作为模型基因，对RNAa的分子本质进行了表征。我们发现，saRNAs引导Ago2至靶启动子并与之结合。装载了saRNA的Ago2促进了RNA诱导的转录激活（RITA）复合物的组装，该复合物除了saRNA-Ago2复合物外，还包括RHA和CTR9，后者是PAF1复合物的一个组分。RITA与RNA聚合酶II相互作用以刺激转录起始和有效的延伸，同时伴随着组蛋白2B的单泛素化。我们的结果证实了细胞中存在一种由RNA引导的基因组靶向和转录激活机制，并为RNAa过程提供了重要的新机制见解。
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