Mechanistic principles of chromatin remodeling guided by siRNAs and miRNAs
Mechanistic principles of chromatin remodeling guided by siRNAs and miRNAs
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DOI：
10.4161/cc.7.16.6541
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发表时间：
2008-08-15
期刊：
影响因子：
4.3
通讯作者：
Serrano, Manuel
中科院分区：
文献类型：
--
作者：
Gonzalez, Susana;Pisano, David G.;Serrano, Manuel
小rna可以引导哺乳动物细胞中的染色质重塑，但其机制尚不清楚。先前的报道已经表明需要重叠转录和Argonaute （Ago）蛋白的参与。在这里，我们使用INK4/ARF基因座的调控结构域（RD）作为sirna引导的染色质重塑易感的实验平台来询问所涉及的机制。我们发现sirna引导的RD的染色质重塑需要重叠转录，并且靶向转录链，而不是模板链，支持小RNA和新生RNA转录物之间的RNA: RNA识别机制。我们发现异染色质的形成既可以由完全匹配的双链RNA前体触发，也可以由不完全匹配的双链RNA前体触发。这些观察结果，加上启动子经常受到重叠转录的事实，开启了mirna也能够指导启动子异染色质形成的可能性。我们证明了这种可能性，表明来自oncomiR簇miR-17-92的miRNAs miR17-5p和miR20a可以诱导启动子的异色特征，这些启动子进行重叠转录并与miRNA种子区具有序列互补。这些结果揭示了mirna基因调控的新水平。
Small RNAs can guide chromatin remodeling in mammalian cells, but the mechanisms involved are poorly understood. Previous reports have shown a requirement for overlapping transcription and the involvement of Argonaute (Ago) proteins. Here, we use the Regulatory Domain (RD) of the INK4/ARF locus as an experimental platform susceptible to siRNA-guided chromatin remodeling to interrogate about the mechanisms involved. We show that siRNA-guided chromatin remodeling of RD requires overlapping transcription, and targets the transcribed strand, but not the template strand, supporting an RNA: RNA recognition mechanism between the small RNA and the nascent RNA transcript. We found that heterochromatin formation can be triggered both by perfectly-matched double-stranded RNA precursors, as well as, by imperfectly-matched double-stranded RNA precursors. These observations, together with the fact that promoters are often subjected to overlapping transcription, open the possibility that miRNAs could also be able to guide heterochromatin formation at promoters. We demonstrate this possibility showing that miRNAs miR17-5p and miR20a from the oncomiR cluster miR-17-92 can induce heterochromatic features in promoters that undergo overlapping transcription and possess sequence complementarity to the miRNA seed region. These results unveil a new level of gene regulation by miRNAs.