Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis
Name
nihms851674.pdf
Size
3.96 MB
Format
Adobe PDF
Checksum (MD5)
c2aa7747a781aecec2a2bf3d40f18112
Author(s)
Suzuki, Hiroshi
Young, Richard A.
Sharp, Phillip A.
Date Issued
March 2017
Journal
Cell
Publisher
Elsevier
Citation
Suzuki, Hiroshi I. et al. “Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis.” Cell 168, 6 (March 2017): 1000–1014 © 2017 Elsevier Inc
Version
Author's final manuscript
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: microRNA; super-enhancer; broad H3K4me3 domain; Drosha; DGCR8; Brd4; cancer
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/J.CELL.2017.02.015
