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
Affiliations
Ahuvi Yearim
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel
Sahar Gelfman
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel
Ronna Shayevitch
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel
Shai Melcer
Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel
Ohad Glaich
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel
Jan-Philipp Mallm
Deutsches Krebsforschungszentrum (DKFZ) and BioQuant, Research Group Genome Organization & Function, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Malka Nissim-Rafinia
Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel
Ayelet-Hashahar S. Cohen
Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel
Karsten Rippe
Deutsches Krebsforschungszentrum (DKFZ) and BioQuant, Research Group Genome Organization & Function, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Eran Meshorer
Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra (Givat Ram) Campus, Jerusalem 91904, Israel
Gil Ast
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel
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.
