HP1 is involved in regulating the global impact of DNA methylation on alternative splicing

Cell Rep. 2015 Feb 24;10(7):1122-34. doi: 10.1016/j.celrep.2015.01.038. Epub 2015 Feb 19.

Abstract

The global impact of DNA methylation on alternative splicing is largely unknown. Using a genome-wide approach in wild-type and methylation-deficient embryonic stem cells, we found that DNA methylation can either enhance or silence exon recognition and affects the splicing of more than 20% of alternative exons. These exons are characterized by distinct genetic and epigenetic signatures. Alternative splicing regulation of a subset of these exons can be explained by heterochromatin protein 1 (HP1), which silences or enhances exon recognition in a position-dependent manner. We constructed an experimental system using site-specific targeting of a methylated/unmethylated gene and demonstrate a direct causal relationship between DNA methylation and alternative splicing. HP1 regulates this gene's alternative splicing in a methylation-dependent manner by recruiting splicing factors to its methylated form. Our results demonstrate DNA methylation's significant global influence on mRNA splicing and identify a specific mechanism of splicing regulation mediated by HP1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Cell Line
  • Chromosomal Proteins, Non-Histone / antagonists & inhibitors
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / deficiency
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Epigenesis, Genetic
  • Exons
  • Genome
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • RNA Interference
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Serine-Arginine Splicing Factors

Substances

  • Chromosomal Proteins, Non-Histone
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Srsf3 protein, mouse
  • heterochromatin-specific nonhistone chromosomal protein HP-1
  • Serine-Arginine Splicing Factors
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • DNA methyltransferase 3B