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Precursor microRNA-122 inhibits synthesis of Insig1 isoform mRNA by modulating polyadenylation site usage

Kara L Norman1, Tzu-Chun Chen1, Gusti Zeiner1

  • 1Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.

RNA (New York, N.Y.)
|September 21, 2017
PubMed

Insights

MicroRNA-122 (miR-122) regulates cholesterol biosynthesis by altering insulin-induced gene 1 (Insig1) mRNA processing. This novel nuclear function of precursor microRNAs impacts Insig1 protein levels and gene expression.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Cholesterol Metabolism

Background:

  • Insig1 protein inhibits cholesterol biosynthesis by targeting SREBP and HMGCR.
  • Liver-specific miR-122 enhances cholesterol biosynthesis through an uncharacterized mechanism.

Purpose of the Study:

  • To elucidate the mechanism by which miR-122 influences cholesterol biosynthesis.
  • To investigate the role of alternative cleavage and polyadenylation in Insig1 mRNA regulation.

Main Methods:

  • Analysis of Insig1 mRNA isoforms generated by alternative cleavage and polyadenylation.
  • Investigating the preferential translation of the short Insig1 mRNA isoform under high cholesterol conditions.
  • Assessing the effect of precursor miR-122 on Insig1 mRNA polyadenylation site usage and protein translation.

Main Results:

  • Insig1 mRNA exists in specific isoforms due to alternative cleavage and polyadenylation.
  • The short 1.4-kb Insig1 mRNA isoform is preferentially translated during high cholesterol.
  • Precursor miR-122 molecules interfere with the promoter-proximal cleavage-polyadenylation site of Insig1 mRNA, down-regulating Insig1 protein.

Conclusions:

  • Precursor miR-122 molecules modulate polyadenylation site usage in Insig1 mRNAs.
  • This modulation leads to decreased Insig1 protein abundance, impacting cholesterol biosynthesis.
  • Precursor microRNAs may possess novel nuclear functions in regulating gene expression.
Keywords:
Insig1cholesterolmRNA isoformsmicroRNApolyadenylation site

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