Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS

Nat Commun. 2020 Sep 21;11(1):4755. doi: 10.1038/s41467-020-18411-x.

Abstract

We hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its biological relevance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cholesterol / metabolism
  • Estrogens / metabolism
  • Gene Expression Regulation
  • Genome-Wide Association Study
  • Heterogeneous-Nuclear Ribonucleoprotein Group C / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group C / metabolism
  • Homeostasis*
  • Humans
  • MCF-7 Cells
  • Oxygen / metabolism*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • RNA, Long Noncoding / physiology*
  • Sterols / biosynthesis*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Estrogens
  • Heterogeneous-Nuclear Ribonucleoprotein Group C
  • RALY protein, human
  • RNA, Long Noncoding
  • Sterols
  • endothelial PAS domain-containing protein 1
  • Cholesterol
  • Oxygen