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

• Published in: Nature communications Vol. 11; no. 1; pp. 4755 - 17
• Main Authors: Wu, Xue, Niculite, Cristina M., Preda, Mihai Bogdan, 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, Davé, Utpal P., Ragoussis, Jiannis, Nephew, Kenneth P., Mari, Bernard, McIntyre, Alan, Konig, Heiko, Ljungman, Mats, Cousminer, Diana L., Macchi, Paolo, Ivan, Mircea
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.09.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 13/109; 13/89; 13/95; 14/32; 38/43; 38/79; 45/15; 45/47; 49/91; 631/337/384/2568; 631/443/319/1557; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biosynthesis; Cell Hypoxia; Cell Line, Tumor; Cell Nucleus - metabolism; Cholesterol; Cholesterol - metabolism; Estrogens; Estrogens - metabolism; Gene Expression Regulation; Genetic diversity; Genome-Wide Association Study; Heterogeneous-Nuclear Ribonucleoprotein Group C - genetics; Heterogeneous-Nuclear Ribonucleoprotein Group C - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Hypoxia; In vivo methods and tests; Loci; MCF-7 Cells; multidisciplinary; Oxygen; Oxygen - metabolism; Phenotype; Phenotypes; Polymorphism, Single Nucleotide; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Long Noncoding - physiology; RNA-binding protein; Science; Science (multidisciplinary); Steroids; Sterols; Sterols - biosynthesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18411-x

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. Noncoding transcripts contribute to the adaptation of cellular processes to oxygen levels. Here the authors characterize a hypoxia responsive lncRNA lincNORS and show that it has a role in cellular sterol homeostasis.