The importance of DNA methylation of exons on alternative splicing

Ronna Shayevitch, Dan Askayo, Ifat Keydar, Gil Ast*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Alternative splicing (AS) contributes to proteome diversity. As splicing occurs cotranscriptionally, epigenetic determinants such as DNA methylation likely play a part in regulation of AS. Previously, we have shown that DNA methylation marks exons and that a loss of DNA methylation alters splicing patterns in a genome-wide manner. To investigate the influence of DNA methylation on splicing of individual genes, we developed a method to manipulate DNA methylation in vivo in a sitespecific manner using the deactivated endonuclease Cas9 fused to enzymes that methylate or demethylate DNA. We used this system to directly change the DNA methylation pattern of selected exons and introns. We demonstrated that changes in the methylation pattern of alternatively spliced exons, but not constitutively spliced exons or introns, altered inclusion levels. This is the first direct demonstration that DNA methylation of exon-encoding regions is directly involved in regulation of AS.

Original languageEnglish
Pages (from-to)1351-1362
Number of pages12
Issue number10
StatePublished - Oct 2018


  • Alternative splicing
  • DNA methylation
  • Splicing regulation


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