LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France.
RNA Biol. 2021 Mar;18(3):404-420. doi: 10.1080/15476286.2020.1812910. Epub 2020 Sep 29.
Long non-coding RNAs (ncRNAs) are major regulators of gene expression and cell fate. The locus encodes the tumour suppressor proteins p15, p16 and p14 required for cell cycle arrest and whose expression increases during senescence. is a ncRNA antisense to the gene. In proliferative cells, prevents senescence by repressing genes through the recruitment of Polycomb-group proteins. In models of replicative and RASval12 oncogene-induced senescence (OIS), the expression of and Polycomb proteins decreases, thus allowing derepression. Here, we found in a model of RAF1 OIS that expression rather increases, due in particular to an increased stability. This led us to search for circular isoforms, as circular RNAs are rather stable species. We found that the expression of two circular increases in several OIS models (RAF1, MEK1 and BRAF). In proliferative cells, they repress expression, while in RAF1 OIS, they promote full induction of and expression. Further analysis of one of these circular shows that it interacts with Polycomb proteins and decreases EZH2 Polycomb protein localization and H3K27me3 at the and promoters, respectively. We propose that changes in the ratio between Polycomb proteins and circular isoforms allow these isoforms to switch from repressors of gene to activators of all genes in RAF1 OIS. Our data reveal that regulation of expression depends on the senescence inducer and underline the importance of circular in the regulation of gene expression and senescence.
长非编码 RNA（lncRNA）是基因表达和细胞命运的主要调控因子。 基因编码细胞周期停滞所必需的肿瘤抑制蛋白 p15、p16 和 p14，其表达在衰老过程中增加。 是 基因的反义 lncRNA。在增殖细胞中， 通过招募多梳蛋白组蛋白来抑制 基因，从而防止衰老。在复制和 RASval12 癌基因诱导衰老（OIS）的模型中， 的表达和多梳蛋白降低，从而允许 去抑制。在这里，我们在 RAF1 OIS 的模型中发现 的表达增加，特别是由于稳定性增加。这促使我们寻找环状 的同种型，因为环状 RNA 是相当稳定的物种。我们发现两种环状 的表达在几种 OIS 模型（RAF1、MEK1 和 BRAF）中增加。在增殖细胞中，它们抑制 表达，而在 RAF1 OIS 中，它们促进 完全诱导表达。对其中一种环状 的进一步分析表明，它与多梳蛋白相互作用，并分别降低 EZH2 多梳蛋白在 和 启动子处的定位和 H3K27me3。我们提出，多梳蛋白和环状 同种型之间的比例变化允许这些同种型从 基因的抑制剂转变为 RAF1 OIS 中所有 基因的激活剂。我们的数据表明， 表达的调节取决于衰老诱导剂，并强调了环状 在 基因表达和衰老调节中的重要性。
