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

doi:10.1016/j.celrep.2015.01.038

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.

Authors

Affiliations

¹ Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
² Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel; Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708, USA.
³ Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel.
⁴ Deutsches Krebsforschungszentrum (DKFZ) and BioQuant, Research Group Genome Organization & Function, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
⁵ Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel. Electronic address: [email protected].
⁶ Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel. Electronic address: [email protected].

PMID: 25704815
DOI: 10.1016/j.celrep.2015.01.038

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
Chromobox Protein Homolog 5
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*
DNA Methyltransferase 3A
DNA Methyltransferase 3B
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
DNMT3A protein, human
RNA, Messenger
RNA, Small Interfering
RNA-Binding Proteins
Srsf3 protein, mouse
Chromobox Protein Homolog 5
Serine-Arginine Splicing Factors
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A