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

Cell. 2017 Mar 9;168(6):1000-1014.e15. doi: 10.1016/j.cell.2017.02.015.

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.

Keywords: Brd4; DGCR8; Drosha; broad H3K4me3 domain; cancer; microRNA; super-enhancer.

Publication types

  • Meta-Analysis

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation
  • Histone Code
  • Humans
  • Mice
  • MicroRNAs / metabolism*
  • Neoplasms / genetics
  • Organ Specificity
  • RNA Processing, Post-Transcriptional / drug effects
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Triazoles / pharmacology

Substances

  • (+)-JQ1 compound
  • Azepines
  • MicroRNAs
  • Transcription Factors
  • Triazoles