Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis

• Main Authors: Suzuki, Hiroshi (Contributor), Young, Richard A. (Author), Sharp, Phillip A. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor), Young, Richard A (Contributor), Sharp, Phillip A (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2018-07-10T14:44:20Z.
• Subjects: Article
• Online Access: Get fulltext

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. Keywords: microRNA; super-enhancer; broad H3K4me3 domain; Drosha; DGCR8; Brd4; cancer
United States. Public Health Service (Grant R01-CA133404)
National Cancer Institute (U.S.) (Grant P30-CA14051)