Histone Marks Regulate the Epithelial-to-Mesenchymal Transition via Alternative Splicing

Histone modifications have long been shown to impact final splicing decisions via modulation of RNA polymerase II elongation rate and/or recruitment of the splicing regulators to their RNA binding sites. However there is little evidence of the driving role of these chromatin modifications in inducing the splicing changes necessary for a switch in the cell’s phenotype. Taking advantage of the epithelial-to-mesenchymal transition (EMT), a reversible cell reprogramming intimately involved in early development and cancer metastasis, we found that dynamic changes in specific histone marks, namely H3K27ac and H3K27me3, were responsible for key splicing changes necessary for EMT. Using CRISPR epigenome editing tools, we showed that a single change in H3K27ac/me3 levels just at the alternatively spliced exon was necessary and sufficient to induce a change in splicing capable of recapitulating important aspects of EMT, such as cell motility and invasiveness. This histone mark-dependent splicing effect was highly dynamic and mediated by direct recruitment of the splicing regulator PTB to its RNA binding sites. Taken together, these results support a novel role for H3K27 marks in inducing a change in the cell’s phenotype via regulation of alternative splicing. We propose the dynamic nature of epigenetic modifications as a rapid, and reversible, mechanism to coordinate the splicing response to cell-extrinsic cues, such as induction of EMT.