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; Mircea Ivan

doi:10.1038/s41467-020-18411-x

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 BuechleinCristina 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, Mircea Ivan

Experimental Therapeutics

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English (US)
Article number	4755
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18411-x
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Wu, X., Niculite, C. M., Preda, M. B., 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., ... Ivan, M. (2020). Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS. Nature communications, 11(1), Article 4755. https://doi.org/10.1038/s41467-020-18411-x

Wu, X, Niculite, CM, Preda, MB, Rossi, A, Tebaldi, T, Butoi, E, White, MK, Tudoran, OM, Petrusca, DN, Jannasch, AS, Bone, WP, Zong, X, Fang, F, Burlacu, A, Paulsen, MT, Hancock, BA, Sandusky, GE, Mitra, S, Fishel, ML, Buechlein, A, Ivan, C, Oikonomopoulos, S, Gorospe, M, Mosley, A, Radovich, M, Davé, UP, Ragoussis, J, Nephew, KP, Mari, B, McIntyre, A, Konig, H, Ljungman, M, Cousminer, DL, Macchi, P & Ivan, M 2020, 'Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS', Nature communications, vol. 11, no. 1, 4755. https://doi.org/10.1038/s41467-020-18411-x

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title = "Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS",

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.",

author = "Xue Wu and Niculite, {Cristina M.} and Preda, {Mihai Bogdan} and Annalisa Rossi and Toma Tebaldi and Elena Butoi and White, {Mattie K.} and Tudoran, {Oana M.} and Petrusca, {Daniela N.} and Jannasch, {Amber S.} and Bone, {William P.} and Xingyue Zong and Fang Fang and Alexandrina Burlacu and Paulsen, {Michelle T.} and Hancock, {Brad A.} and Sandusky, {George E.} and Sumegha Mitra and Fishel, {Melissa L.} and Aaron Buechlein and Cristina Ivan and Spyros Oikonomopoulos and Myriam Gorospe and Amber Mosley and Milan Radovich and Dav{\'e}, {Utpal P.} and Jiannis Ragoussis and Nephew, {Kenneth P.} and Bernard Mari and Alan McIntyre and Heiko Konig and Mats Ljungman and Cousminer, {Diana L.} and Paolo Macchi and Mircea Ivan",

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doi = "10.1038/s41467-020-18411-x",

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AU - Wu, Xue

AU - Niculite, Cristina M.

AU - Preda, Mihai Bogdan

AU - Rossi, Annalisa

AU - Tebaldi, Toma

AU - Butoi, Elena

AU - White, Mattie K.

AU - Tudoran, Oana M.

AU - Petrusca, Daniela N.

AU - Jannasch, Amber S.

AU - Bone, William P.

AU - Zong, Xingyue

AU - Fang, Fang

AU - Burlacu, Alexandrina

AU - Paulsen, Michelle T.

AU - Hancock, Brad A.

AU - Sandusky, George E.

AU - Mitra, Sumegha

AU - Fishel, Melissa L.

AU - Buechlein, Aaron

AU - Ivan, Cristina

AU - Oikonomopoulos, Spyros

AU - Gorospe, Myriam

AU - Mosley, Amber

AU - Radovich, Milan

AU - Davé, Utpal P.

AU - Ragoussis, Jiannis

AU - Nephew, Kenneth P.

AU - Mari, Bernard

AU - McIntyre, Alan

AU - Konig, Heiko

AU - Ljungman, Mats

AU - Cousminer, Diana L.

AU - Macchi, Paolo

AU - Ivan, Mircea

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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

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