Institute of Human Genetics, University of Montpellier, Centre National de la Recherche Scientifique, Montpellier, France.
Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UK.
Cell Rep. 2022 Feb 15;38(7):110357. doi: 10.1016/j.celrep.2022.110357.
Histone modifications impact final splicing decisions. However, there is little evidence of the driving role of these marks in inducing cell-specific splicing changes. Using CRISPR epigenome editing tools, we show in an epithelial-to-mesenchymal cell reprogramming system (epithelial-to-mesenchymal transition [EMT]) that a single change in H3K27ac or H3K27me3 levels right at the alternatively spliced exon is necessary and sufficient to induce a splicing change capable of recapitulating important aspects of EMT, such as cell motility and invasiveness. This histone-mark-dependent splicing effect is highly dynamic and mediated by direct recruitment of the splicing regulator PTB to its RNA binding sites. These results support a role for H3K27 marks in inducing a change in the cell's phenotype via regulation of alternative splicing. We propose the dynamic nature of chromatin as a rapid and reversible mechanism to coordinate the splicing response to cell-extrinsic cues, such as induction of EMT.
组蛋白修饰影响最终的剪接决定。然而，这些标记在诱导细胞特异性剪接变化中的驱动作用的证据很少。使用 CRISPR 表观基因组编辑工具，我们在一个上皮细胞到间充质细胞重编程系统（上皮细胞到间充质转化 [EMT]）中表明，在选择性剪接外显子处单个 H3K27ac 或 H3K27me3 水平的变化足以诱导剪接变化，能够再现 EMT 的重要方面，如细胞迁移和侵袭性。这种依赖于组蛋白标记的剪接效应是高度动态的，并通过剪接调节剂 PTB 直接募集到其 RNA 结合位点来介导。这些结果支持 H3K27 标记在通过调节选择性剪接来诱导细胞表型变化中的作用。我们提出染色质的动态性质是一种快速和可逆的机制，用于协调对细胞外信号（如 EMT 诱导）的剪接反应。
