期刊
CELL REPORTS
卷 10, 期 7, 页码 1122-1134出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.01.038
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资金
- Israel Science Foundation [ISF-Bikura 838/10, ISF 61/09, ISF 1252/12, 657/12]
- Israel Cancer Research Foundation [ICRF PG-14/195]
- Israel Science Foundation FIRST individual grant [ISF 1430/13]
- Abisch-Frenkel Foundation
- Israel-Germany MOST-DKFZ collaboration grant
- European Research Council FP7 grant [ERC-281781]
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.
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