Janowski Bethany A, Huffman Kenneth E, Schwartz Jacob C, Ram Rosalyn, Nordsell Robert, Shames David S, Minna John D, Corey David R
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
Nat Struct Mol Biol. 2006 Sep;13(9):787-92. doi: 10.1038/nsmb1140. Epub 2006 Aug 27.
Duplex RNAs complementary to messenger RNA inhibit translation in mammalian cells by RNA interference (RNAi). Studies have reported that RNAs complementary to promoter DNA also inhibit gene expression. Here we show that the human homologs of Argonaute-1 (AGO1) and Argonaute-2 (AGO2) link the silencing pathways that target mRNA with pathways mediating recognition of DNA. We find that synthetic antigene RNAs (agRNAs) complementary to transcription start sites or more upstream regions of gene promoters inhibit gene transcription. This silencing occurs in the nucleus, requires high promoter activity and does not necessarily require histone modification. AGO1 and AGO2 associate with promoter DNA in cells treated with agRNAs, and inhibiting expression of AGO1 or AGO2 reverses transcriptional and post-transcriptional silencing. Our data indicate key linkages and important mechanistic distinctions between transcriptional and post-transcriptional silencing pathways in mammalian cells.
与信使核糖核酸互补的双链核糖核酸通过RNA干扰（RNAi）抑制哺乳动物细胞中的翻译。研究报告称，与启动子DNA互补的核糖核酸也会抑制基因表达。在此我们表明，AGO1（Argonaute-1）和AGO2（Argonaute-2）的人类同源物将靶向信使核糖核酸的沉默途径与介导DNA识别的途径联系起来。我们发现，与基因启动子转录起始位点或更上游区域互补的合成反基因核糖核酸（agRNAs）会抑制基因转录。这种沉默发生在细胞核中，需要高启动子活性，且不一定需要组蛋白修饰。在经agRNAs处理的细胞中，AGO1和AGO2与启动子DNA结合，抑制AGO1或AGO2的表达会逆转转录沉默和转录后沉默。我们的数据表明了哺乳动物细胞中转录沉默和转录后沉默途径之间的关键联系和重要机制差异。
