Characterization of tissue-specific differential DNA methylation suggests distinct modes of positive and negative gene expression regulation

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• 作者：Jun Wan (1)
  Verity F Oliver (1)
  Guohua Wang (1)
  Heng Zhu (2)
  Donald J Zack (1) (3) (4) (5) (6)
  Shannath L Merbs (1)
  Jiang Qian (1)
  
  1. Department of Ophthalmology ; Wilmer Institute ; Johns Hopkins University School of Medicine ; Baltimore ; MA ; USA
  2. Department of Pharmacology and Molecular Science ; Johns Hopkins University School of Medicine ; Baltimore ; MA ; USA
  3. Department of Molecular Biology and Genetics ; Johns Hopkins University School of Medicine ; Baltimore ; MA ; USA
  4. Department of Neuroscience ; Johns Hopkins University School of Medicine ; Baltimore ; MA ; USA
  5. Institute of Genetic Medicine ; Johns Hopkins University School of Medicine ; Baltimore ; MA ; USA
  6. Institut de la Vision ; Universit茅 Pierre et Marie Curie ; 17 rue Moreau ; Paris ; France
  
• 关键词：DNA methylation ; Tissue ; specific ; Differentially methylated region ; Gene regulation
• 刊名：BMC Genomics
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：16
• 期：1
• 全文大小：1,944 KB
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• 刊物主题：Life Sciences, general; Microarrays; Proteomics; Animal Genetics and Genomics; Microbial Genetics and Genomics; Plant Genetics & Genomics;
• 出版者：BioMed Central
• ISSN：1471-2164

文摘

Background DNA methylation plays an important role in regulating gene expression during many biological processes. However, the mechanism of DNA-methylation-dependent gene regulation is not fully understood. Here, we explore two possible DNA methylation regulatory mechanisms with opposite modes of gene expression regulation. Results By comparing the genome-wide methylation and expression patterns in different tissues, we find that majority of tissue-specific differentially methylated regions (T-DMRs) are negatively correlated with expression of their associated genes (negative T-DMRs), consistent with the classical dogma that DNA methylation suppresses gene expression; however, a significant portion of T-DMRs are positively correlated with gene expression (positive T-DMRs). We observe that the positive T-DMRs have similar genomic location as negative T-DMRs, except that the positive T-DMRs are more enriched in the promoter regions. Both positive and negative T-DMRs are enriched in DNase I hypersensitivity sites (DHSs), suggesting that both are likely to be functional. The CpG sites of both positive and negative T-DMRs are also more evolutionarily conserved than the genomic background. Interestingly, the putative target genes of the positive T-DMR are enriched for negative regulators such as transcriptional repressors, suggesting a novel mode of indirect DNA methylation inhibition of expression through transcriptional repressors. Likewise, two distinct sets of DNA sequence motifs exist for positive and negative T-DMRs, suggesting that two distinct sets of transcription factors (TFs) are involved in positive and negative regulation mediated by DNA methylation. Conclusions We find both negative and positive association between T-DMRs and gene expression, which implies the existence of two different mechanisms of DNA methylation-dependent gene regulation.