HP1 Is Involved in Regulating the Global Impact of DNA Methylation on Alternative Splicing

Ahuvi Yearim, Sahar Gelfman, Ronna Shayevitch, Shai Melcer, Ohad Glaich, Jan Philipp Mallm, Malka Nissim-Rafinia, Ayelet Hashahar S. Cohen, Karsten Rippe, Eran Meshorer*, Gil Ast

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1122-1134
Number of pages13
JournalCell Reports
Volume10
Issue number7
DOIs
StatePublished - 24 Feb 2015

Funding

FundersFunder number
Israel Cancer Research Fund657/12, ICRF PG-14/195, ISF 1252/12, ISF 1430/13
Seventh Framework Programme281781
European Research Council
Israel Science FoundationISF 61/09, ISF-Bikura 838/10
Abisch-Frenkel-Stiftung

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