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

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. 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.

我们在此提供了lincNORS的初步特征描述，它是一种由MIR193BHG基因座产生的剪接长链非编码RNA（lincRNA），与先前描述的miR - 193b - 365a串联体完全不同。虽然它在多种细胞中可由低氧诱导且在体内与缺氧相关，但我们的研究表明，lincNORS受到多种调控输入的影响，包括雌激素信号。从生化角度来看，这种lincRNA通过抑制多种通路组分的表达来微调细胞内固醇/类固醇的生物合成。从机制上讲，lincNORS的功能需要RALY的存在，RALY是一种最近发现与胆固醇稳态有关的RNA结合蛋白。我们还注意到该基因座与对固醇/类固醇相关表型（特别是性成熟年龄）具有高度显著影响的自然发生的遗传变异之间的邻近性。对这些变异的综合分析在这些表型和lincNORS之间提供了更正式的联系，进一步强化了其生物学相关性的依据。 非编码转录本有助于细胞过程对氧水平的适应。在此，作者对一种缺氧反应性长链非编码RNA（lncRNA）lincNORS进行了表征，并表明它在细胞固醇稳态中具有作用。