Histone marks regulate the epithelial-to-mesenchymal transition via alternative splicing

Alexandre Segelle, Yaiza Núñez-Álvarez, Andrew J. Oldfield, Kimberly M. Webb, Philipp Voigt, Reini F. Luco*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number110357
Number of pages36
JournalCell Reports
Volume38
Issue number7
DOIs
Publication statusPublished - 15 Feb 2022

Keywords

  • alternative splicing
  • chromatin
  • CRISPR
  • EMT
  • epigenome editing
  • epithelial-to-mesenchymal transition
  • H3K27
  • histone modifications

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