Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS
Xue Wu, Cristina Niculiţe, Mihai Bogdan Preda, Annalisa Rossi, Toma Tebaldi, Elena Butoi, Mattie White, Oana Tudoran, Daniela N. Petrusca, Amber S. Jannasch, William P. Bone, Xingyue Zong, Fang Fang, Alexandrina Burlacu, Michelle T. Paulsen, Brad Hancock, George E. Sandusky, Sumegha Mitra, Melissa L. Fishel, Aaron Buechlein, Cristina Ivan, Spyros Oikonomopoulos, Myriam Gorospe, Amber L. Mosley, Milan Radovich, Utpal P. Davé, Jiannis Ragoussis, Kenneth P. Nephew, Bernard Mari, Alan McIntyre, Heiko Konig, Mats Ljungman, Diana L. Cousminer, Paolo Macchi, Mircea Ivan
Abstract
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 O 2 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.