title: HP1 is involved in regulating the global impact of DNA methylation on alternative splicing.
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.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Ahuvi
authors.initials: A
authors.lastname: Yearim
authors.affiliation: 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.
authors.forename: Sahar
authors.initials: S
authors.lastname: Gelfman
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Ronna
authors.initials: R
authors.lastname: Shayevitch
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Melcer
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Ohad
authors.initials: O
authors.lastname: Glaich
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ) and BioQuant, Research Group Genome Organization & Function, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Jan-Philipp
authors.initials: JP
authors.lastname: Mallm
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel.
authors.forename: Malka
authors.initials: M
authors.lastname: Nissim-Rafinia
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel.
authors.forename: Ayelet-Hashahar S
authors.initials: AH
authors.lastname: Cohen
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ) and BioQuant, Research Group Genome Organization & Function, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Rippe
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel. Electronic address: meshorer@huji.ac.il.
authors.forename: Eran
authors.initials: E
authors.lastname: Meshorer
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel. Electronic address: gilast@post.tau.ac.il.
authors.forename: Gil
authors.initials: G
authors.lastname: Ast
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005091:Exons; D016678:Genome; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D000097584:DNA Methyltransferase 3B
chemical_list: D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C106161:Srsf3 protein, mouse