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.

A human adipose tissue cell-type transcriptome atlas

“…In our analysis, adipocytes had the most enriched non-coding genes, including antisense transcripts to adipocyte-enriched protein-coding genes, e.g., ALDH1L1-AS2, ADIPOQ-AS1, LIPE-AS1, and CNTFR-AS1. Other adipocyte-enriched non-coding genes included RP11-863K10.7, an antisense transcript to ERLIN2, a gene with a role in the accumulation of cytosolic lipid droplets (Wang et al, 2012); MIRLET7BHG, which is important for adipocyte differentiation in mice (McGregor and Choi, 2011;Sun et al, 2009); and MIR193BHG, which was characterized as a cellular steroid biosynthesis pathway modulator in MCF7 cells (Wu et al, 2020). Mesothelial-cell-enriched non-coding genes included antisense transcripts to mesothelial-enriched protein-coding genes, e.g., SEMA3B-AS, DPP10-AS1, FAM83H-AS1, and WT1-AS1.…”

Prognostication of Pancreatic Cancer Using The Cancer Genome Atlas Based Ferroptosis-Related Long Non-Coding RNAs

“…AC099850.3 has been repeatedly extracted as a prognosis-related gene in the bioinformatics analysis of cancer, including squamous cell carcinoma of the tongue, hepatocellular carcinoma, and non-small cell lung cancer ( Hao Wu et al, 2020 ; Jia et al, 2020 ; Zheng et al, 2021a ; Junliang Zhou et al, 2021 ; Jiang et al, 2021 ; Wu et al, 2021 ; Xu et al, 2021 ; Zhang et al, 2021 ). The MIR193BHG motif can fine-tune cellular sterol/steroid biosynthesis by producing lincNORS to repress the expression of multiple pathway components ( Xue Wu et al, 2020 ). MIR193BHG was found to be significantly associated with the prognosis in both autophagy-related lncRNA in ovarian cancer and ferroptosis-related lncRNA in lung adenocarcinoma ( Chan Meng et al, 2020 ; Zheng et al, 2021b ).…”

Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase

“…Cholesterol synthesis is a particularly resource-intensive pathway, requiring eleven oxygen molecules and over one hundred ATP equivalents per molecule of product, yet there are conflicting reports on changes in overall flux from acetyl-CoA to cholesterol during hypoxia [24, 25], indicative of cell type-specific responses. Nevertheless, the small number of studies into individual biosynthetic enzymes indicate that their activity is suppressed by hypoxia at multiple regulatory levels, which is supported by the accumulation of various pathway intermediates [26, 27, 58]. Lanosterol demethylase, which requires three oxygen molecules for catalysis, is transcriptionally downregulated by HIF2α and the hypoxia-induced long non-coding RNA lincNORS , contributing to the characteristic accumulation of lanosterol under hypoxic conditions [26, 59].…”

“…Nevertheless, the small number of studies into individual biosynthetic enzymes indicate that their activity is suppressed by hypoxia at multiple regulatory levels, which is supported by the accumulation of various pathway intermediates [26, 27, 53]. Lanosterol demethylase, which requires three oxygen molecules for catalysis, is transcriptionally downregulated by HIF2α and the hypoxia-induced long non-coding RNA lincNORS , contributing to the characteristic accumulation of lanosterol under hypoxic conditions [26, 54]. Lanosterol in turn triggers the ubiquitin-dependent degradation of the early cholesterol synthesis enzyme HMGCR [27], suppressing further oxygen consumption by the pathway.…”