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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
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Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis.

Hiroshi I Suzuki1, Richard A Young2, Phillip A Sharp3

  • 1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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|March 12, 2017
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Super-enhancers drive master microRNA (miRNA) production by enhancing transcription and processing. These regulatory regions also influence miRNA networks and are linked to cancer hallmarks.

Keywords:
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Area of Science:

  • Genomics
  • Molecular Biology
  • Epigenetics

Background:

  • Super-enhancers are key regulatory elements controlling cell identity and disease genes.
  • The precise role of super-enhancers in microRNA (miRNA) networks remains largely unknown.

Purpose of the Study:

  • To investigate the function of super-enhancers in miRNA biogenesis and their impact on cellular identity and disease.
  • To elucidate the mechanisms by which super-enhancers regulate miRNA transcription and processing.

Main Methods:

  • CRISPR/Cas9 genome editing to analyze super-enhancer function.
  • Analysis of H3K4me3 domains and their correlation with miRNA expression.
  • Treatment with BET-bromodomain inhibitor JQ1 to assess effects on super-enhancer activity.
  • Investigation of interactions between super-enhancers, DGCR8/Drosha complex, and mRNA stability.

Main Results:

  • Super-enhancers enhance both transcription and Drosha/DGCR8-mediated processing of primary miRNAs (pri-miRNAs).
  • Super-enhancers, alongside H3K4me3 domains, establish a tissue-specific and conserved miRNA expression atlas.
  • Super-enhancer constituents cooperate to recruit Drosha/DGCR8, boosting miRNA production.
  • Super-enhancers exhibit interactions with DGCR8/Drosha and regulate mRNA stability, indicating novel RNA processing roles.
  • Super-enhancers are associated with miRNAs implicated in cancer hallmarks.

Conclusions:

  • Super-enhancers play a critical role in miRNA biogenesis, influencing cell identity and disease pathways.
  • This study reveals an unrecognized function of super-enhancers in RNA processing beyond transcriptional control.
  • Super-enhancers represent a significant regulatory layer in miRNA biology, with implications for understanding health and disease.