title: Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis.
abstract: 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.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Hiroshi I
authors.initials: HI
authors.lastname: Suzuki
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: sharppa@mit.edu.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Sharp
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D042421:Histone Code; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics; D009928:Organ Specificity; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014230:Triazoles / Q000494:pharmacology
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D035683:MicroRNAs; D014157:Transcription Factors; D014230:Triazoles
keywords: Brd4; DGCR8; Drosha; broad H3K4me3 domain; cancer; microRNA; super-enhancer