The alternative role of DNA methylation in splicing regulation

Trends Genet. 2015 May;31(5):274-80. doi: 10.1016/j.tig.2015.03.002. Epub 2015 Mar 30.


Although DNA methylation was originally thought to only affect transcription, emerging evidence shows that it also regulates alternative splicing. Exons, and especially splice sites, have higher levels of DNA methylation than flanking introns, and the splicing of about 22% of alternative exons is regulated by DNA methylation. Two different mechanisms convey DNA methylation information into the regulation of alternative splicing. The first involves modulation of the elongation rate of RNA polymerase II (Pol II) by CCCTC-binding factor (CTCF) and methyl-CpG binding protein 2 (MeCP2); the second involves the formation of a protein bridge by heterochromatin protein 1 (HP1) that recruits splicing factors onto transcribed alternative exons. These two mechanisms, however, regulate only a fraction of such events, implying that more underlying mechanisms remain to be found.

Keywords: CpG; DNA methylation; alternative splicing; chromatin organization; histone modifications; nucleosome positioning; transcription.

Publication types

  • Review

MeSH terms

  • Alternative Splicing
  • Animals
  • CCCTC-Binding Factor
  • Chromobox Protein Homolog 5
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Methylation*
  • Exons
  • Gene Expression Regulation*
  • Humans
  • Methyl-CpG-Binding Protein 2 / metabolism
  • RNA Splicing*
  • Repressor Proteins / metabolism


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Chromosomal Proteins, Non-Histone
  • Methyl-CpG-Binding Protein 2
  • Repressor Proteins
  • Chromobox Protein Homolog 5