Abstract
The exact role of intragenic DNA methylation in regulating tissue-specific gene regulation is unclear. Recently, the DNA-binding protein CTCF has been shown to participate in the regulation of alternative splicing in a DNA methylation-dependent manner. To globally evaluate the relationship between DNA methylation and tissue-specific alternative splicing, we performed genome-wide DNA methylation profiling of mouse retina and brain. In protein-coding genes, tissue-specific differentially methylated regions (T-DMRs) were preferentially located in exons and introns. Gene ontology and evolutionary conservation analysis suggest that these T-DMRs are likely to be biologically relevant. More than 14% of alternatively spliced genes were associated with a T-DMR. T-DMR-associated genes were enriched for developmental genes, suggesting that a specific set of alternatively spliced genes may be regulated through DNA methylation. Novel DNA sequences motifs overrepresented in T-DMRs were identified as being associated with positive and/or negative regulation of alternative splicing in a position-dependent context. The majority of these evolutionarily conserved motifs contain a CpG dinucleotide. Some transcription factors, which recognize these motifs, are known to be involved in splicing. Our results suggest that DNA methylation-dependent alternative splicing is widespread and lay the foundation for further mechanistic studies of the role of DNA methylation in tissue-specific splicing regulation.
Highlights
DNA methylation plays an important role in the epigenetic regulation of gene expression; yet, the exact mechanisms by which DNA methylation affects transcriptional regulation are not fully understood
22.0% of the 2498 tissue-specific differentially methylated regions (T-DMRs) identified between mouse retina and brain were intergenic, demonstrating a significant overrepresentation compared with percentage of all probes within the intergenic region based on the comprehensive high-throughput array for relative methylation (CHARM) array design (20.7%; P = 6.4 Â 10À6)
The majority of gene-associated T-DMR probes were located in exons (17.8%) and introns (45.3%), which were significantly overrepresented (12.2 and 39.5%, respectively; P = 0, Figure 1A), suggesting that DNA methylation might play an important role in regulating alternative splicing
Summary
DNA methylation plays an important role in the epigenetic regulation of gene expression; yet, the exact mechanisms by which DNA methylation affects transcriptional regulation are not fully understood. The remaining CpG islands are dispersed between intra- and intergenic regions [2]; unlike the CpG islands that overlap promoters, methylation of these regions is not necessarily associated with gene silencing [3]. De novo methylation at intra- and intergenic CpG islands has been hypothesized to play an important role in tissue differentiation by controlling gene expression in a time-dependent manner [2]. This hypothesis is supported by evidence suggesting that >40% of intra- and intergenic CpG islands in the human and mouse overlap with sites of transcription
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