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

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 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. Overall design: Examination of primary transcript level using the nascent RNA Bru-seq method, in MCF-7 cells cultured under normoxia (21% O2) or hypoxia (1% O2).