整合性微小RNA网络分析揭示的超级增强子介导的RNA加工
Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis.
作者信息
Suzuki Hiroshi I, Young Richard A, Sharp Phillip A
机构信息
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
出版信息
Cell. 2017 Mar 9;168(6):1000-1014.e15. doi: 10.1016/j.cell.2017.02.015.
Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancer-directed cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAs associated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and an unrecognized higher-order property of super-enhancers in RNA processing beyond transcription.
超级增强子是一类新兴的调控区域亚类，控制着细胞身份和疾病相关基因。然而，它们的生物学功能以及对miRNA网络的影响尚不清楚。在此，我们报告称，超级增强子通过增强转录以及Drosha/DGCR8介导的初级miRNA（pri-miRNA）加工过程，驱动对细胞身份至关重要的主要miRNA的生物合成。超级增强子与广泛的H3K4me3结构域共同塑造了一个组织特异性且在进化上保守的miRNA表达和功能图谱。CRISPR/Cas9基因组学研究表明，超级增强子的组成成分协同发挥作用，并促进Drosha/DGCR8的招募以及pri-miRNA的加工，从而提高细胞特异性miRNA的产生。BET-溴结构域抑制剂JQ1优先抑制超级增强子导向的共转录pri-miRNA加工过程。此外，超级增强子的特征是与DGCR8/Drosha广泛相互作用以及对DGCR8/Drosha调控的mRNA稳定性进行控制，这表明超级增强子存在独特的RNA调控机制。最后，超级增强子标记了多个与癌症特征相关的miRNA。这项研究揭示了健康和疾病状态下miRNA生物学的潜在原理，以及超级增强子在转录之外的RNA加工过程中一种未被认识的高阶特性。
Zotero 插件