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Accession IconSRP052235

HP1 is involved in regulating the global impact of DNA methylation on alternative splicing

Organism Icon Mus musculus
Sample Icon 14 Downloadable Samples
Technology Badge IconIllumina Genome Analyzer II, Illumina HiSeq 2000

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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 act both as an enhancer and as a silencer of splicing, 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. Overall design: BS-seq on WT mouse ES cells (2 replicates), MNase-seq on WT and TKO cells (3 replicates), mRNA-seq on WT and TKO cells as well as HP1 knock-down cells (2 replicates for each sample)
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