Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
Nat Commun. 2019 Nov 13;10(1):5137. doi: 10.1038/s41467-019-12970-4.
RNA has been classically known to play central roles in biology, including maintaining telomeres, protein synthesis, and in sex chromosome compensation. While thousands of long noncoding RNAs (lncRNAs) have been identified, attributing RNA-based roles to lncRNA loci requires assessing whether phenotype(s) could be due to DNA regulatory elements, transcription, or the lncRNA. Here, we use the conserved X chromosome lncRNA locus Firre, as a model to discriminate between DNA- and RNA-mediated effects in vivo. We demonstrate that (i) Firre mutant mice have cell-specific hematopoietic phenotypes, and (ii) upon exposure to lipopolysaccharide, mice overexpressing Firre exhibit increased levels of pro-inflammatory cytokines and impaired survival. (iii) Deletion of Firre does not result in changes in local gene expression, but rather in changes on autosomes that can be rescued by expression of transgenic Firre RNA. Together, our results provide genetic evidence that the Firre locus produces a trans-acting lncRNA that has physiological roles in hematopoiesis.
RNA 在生物学中发挥着核心作用，包括维持端粒、蛋白质合成和性染色体补偿。尽管已经鉴定出数千种长非编码 RNA（lncRNA），但将基于 RNA 的作用归因于 lncRNA 基因座需要评估表型是否可能归因于 DNA 调控元件、转录或 lncRNA。在这里，我们使用保守的 X 染色体 lncRNA 基因座 Firre 作为模型，在体内区分 DNA 和 RNA 介导的效应。我们证明了 (i) Firre 突变小鼠具有细胞特异性造血表型，以及 (ii) 在暴露于脂多糖后，过表达 Firre 的小鼠表现出更高水平的促炎细胞因子和生存能力受损。(iii) Firre 的缺失不会导致局部基因表达的变化，而是导致常染色体上的变化，这些变化可以通过表达转基因 Firre RNA 来挽救。总之，我们的结果提供了遗传证据，表明 Firre 基因座产生了一种具有生理作用的反式作用 lncRNA 在造血中。
