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

Wu, Xue; Niculite, Cristina M.; Bogdan Preda, Mihai; Rossi, Annalisa; Tebaldi, Toma; Butoi, Elena; White, Mattie K.; Tudoran, Oana M.; Petrusca, Daniela N.; Jannasch, Amber S.; Bone, William P.; Zong, Xingyue; Fang, Fang; Burlacu, Alexandrina; Paulsen, Michelle T.; Hancock, Brad A.; Sandusky, George E.; Mitra, Sumegha; Fishel, Melissa L.; Buechlein, Aaron; Ivan, Cristina; Oikonomopoulos, Spyros; Gorospe, Myriam; Mosley, Amber; Radovich, Milan; Dav�, Utpal P.; Ragoussis, Jiannis; Nephew, Kenneth P.; Mari, Bernard; McIntyre, Alan; Konig, Heiko; Ljungman, Mats; Cousminer, Diana L.; Macchi, Paolo; Ivan, Mircea

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.

Citation

Wu, X., Niculite, C. M., Bogdan Preda, M., Rossi, A., Tebaldi, T., Butoi, E., White, M. K., Tudoran, O. M., Petrusca, D. N., Jannasch, A. S., Bone, W. P., Zong, X., Fang, F., Burlacu, A., Paulsen, M. T., Hancock, B. A., Sandusky, G. E., Mitra, S., Fishel, M. L., Buechlein, A., …Ivan, M. (2020). Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS. Nature Communications, 11, Article 4755. https://doi.org/10.1038/s41467-020-18411-x

• Journal Article Type: Article
• Acceptance Date: Aug 16, 2020
• Online Publication Date: Sep 21, 2020
• Publication Date: 2020-12
• Deposit Date: Sep 15, 2020
• Publicly Available Date: Sep 30, 2020
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Article Number: 4755
• DOI: https://doi.org/10.1038/s41467-020-18411-x
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/4780801
• Publisher URL: https://www.nature.com/articles/s41467-020-18411-x