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

Hiroshi Suzuki | Zendy; Richard A. Young | Zendy; Phillip A. Sharp | Zendy

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

Author(s) -

Hiroshi Suzuki,

Richard A. Young,

Phillip A. Sharp

Publication year - 2017

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2017.02.015

Subject(s) - drosha , biology , enhancer , microrna , enhancer rnas , crispr , computational biology , genetics , cas9 , rna , microbiology and biotechnology , transcription factor , rna interference , gene

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.

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