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

Xue Wu, Cristina M. Niculite, Mihai Bogdan Preda, Annalisa Rossi, Toma Tebaldi, Elena Butoi, Mattie K. White, Oana M. Tudoran, Daniela N. Petrusca, Amber S. Jannasch, William P. Bone, Xingyue Zong, Fang Fang, Alexandrina Burlacu, Michelle T. Paulsen, Brad A. Hancock, George E. Sandusky, Sumegha Mitra, Melissa L. Fishel, Aaron Buechlein, Cristina Ivan, Spyros Oikonomopoulos, Myriam Gorospe, Amber Mosley, Milan Radovich, Utpal P. Davé, Jiannis Ragoussis, Kenneth P. Nephew, Bernard Mari, Alan McIntyre, Heiko Konig, Mats Ljungman, Diana L. Cousminer, Paolo Macchi and Mircea Ivan ()
Additional contact information
Xue Wu: Indiana University School of Medicine
Cristina M. Niculite: Indiana University School of Medicine
Mihai Bogdan Preda: Institute of Cellular Biology and Pathology “Nicolae Simionescu”
Annalisa Rossi: Computational and Integrative Biology - CIBIO, University of Trento
Toma Tebaldi: Computational and Integrative Biology - CIBIO, University of Trento
Elena Butoi: Institute of Cellular Biology and Pathology “Nicolae Simionescu”
Mattie K. White: Indiana University School of Medicine
Oana M. Tudoran: The Oncology Institute “Prof Dr. Ion Chiricuta”
Daniela N. Petrusca: Indiana University School of Medicine
Amber S. Jannasch: Purdue University
William P. Bone: University of Pennsylvania
Xingyue Zong: Indiana University School of Medicine
Fang Fang: Indiana University School of Medicine
Alexandrina Burlacu: Institute of Cellular Biology and Pathology “Nicolae Simionescu”
Michelle T. Paulsen: Center for RNA Biomedicine, University of Michigan
Brad A. Hancock: Indiana University School of Medicine
George E. Sandusky: Indiana University School of Medicine
Sumegha Mitra: Indiana University
Melissa L. Fishel: Indiana University
Aaron Buechlein: Indiana University Center for Genomics and Bioinformatics
Cristina Ivan: The University of Texas MD Anderson Cancer Center
Spyros Oikonomopoulos: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, McGill University
Myriam Gorospe: National Institutes of Health
Amber Mosley: Indiana University School of Medicine
Milan Radovich: Center for RNA Biomedicine, University of Michigan
Utpal P. Davé: Indiana University School of Medicine
Jiannis Ragoussis: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, McGill University
Kenneth P. Nephew: Indiana University School of Medicine
Bernard Mari: CNRS, IPMC, FHU-OncoAge, Université Côte d’Azur
Alan McIntyre: University of Michigan
Heiko Konig: Indiana University School of Medicine
Mats Ljungman: Center for RNA Biomedicine, University of Michigan
Diana L. Cousminer: University of Pennsylvania
Paolo Macchi: Computational and Integrative Biology - CIBIO, University of Trento
Mircea Ivan: Indiana University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-17

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 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.

Date: 2020
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DOI: 10.1038/s41467-020-18411-x

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