title: Integrative analysis of tissue-specific methylation and alternative splicing identifies conserved transcription factor binding motifs.
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.
authors.affiliation: Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, 21287 Baltimore, MD, USA, Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, 600 North Wolfe Street, 21287 Baltimore, MD, USA, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 600 North Wolfe Street, 21287 Baltimore, MD, USA, Department of Neuroscience, Johns Hopkins University School of Medicine, 600 North Wolfe Street, 21287 Baltimore, MD, USA, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 600 North Wolfe Street, 21287 Baltimore, MD, USA and Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.forename: Verity F
authors.initials: VF
authors.lastname: Oliver
authors.forename: Heng
authors.initials: H
authors.lastname: Zhu
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Shannath L
authors.initials: SL
authors.lastname: Merbs
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D017124:Conserved Sequence; D004247:DNA / Q000737:chemistry*; D019175:DNA Methylation; D019143:Evolution, Molecular; D005091:Exons; D007438:Introns; D051379:Mice; D008810:Mice, Inbred C57BL; D059372:Nucleotide Motifs; D009928:Organ Specificity; D011506:Proteins / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D012160:Retina / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D011506:Proteins; D014157:Transcription Factors; D004247:DNA