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.
Nucleic Acids Res. 2013 Oct;41(18):8503-14. doi: 10.1093/nar/gkt652. Epub 2013 Jul 24.
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.
内源性 DNA 甲基化在调节组织特异性基因调控中的确切作用尚不清楚。最近，DNA 结合蛋白 CTCF 被证明以依赖于 DNA 甲基化的方式参与调节可变剪接。为了全面评估 DNA 甲基化与组织特异性可变剪接之间的关系，我们对小鼠视网膜和大脑进行了全基因组 DNA 甲基化谱分析。在蛋白质编码基因中，组织特异性差异甲基化区域 (T-DMR) 优先位于外显子和内含子中。基因本体论和进化保守性分析表明，这些 T-DMR 可能具有生物学意义。超过 14%的可变剪接基因与 T-DMR 相关。T-DMR 相关基因富集了发育基因，表明一组特定的可变剪接基因可能通过 DNA 甲基化进行调节。在位置依赖性背景下，鉴定出在 T-DMR 中过度表达的新型 DNA 序列基序与可变剪接的正调节和/或负调节相关。这些进化上保守的基序大多数含有 CpG 二核苷酸。一些识别这些基序的转录因子，已知参与剪接。我们的研究结果表明，DNA 甲基化依赖的可变剪接很普遍，并为进一步研究 DNA 甲基化在组织特异性剪接调控中的作用的机制研究奠定了基础。
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