title: Characterization of tissue-specific differential DNA methylation suggests distinct modes of positive and negative gene expression regulation.
abstract: 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.
authors: Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MA, USA. jun.wan@jhmi.edu.
authors: Jun
authors: J
authors: Wan
authors: Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MA, USA. verityoliver@gmail.com.
authors: Verity F
authors: VF
authors: Oliver
authors: Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MA, USA. gwang8@jhmi.edu.
authors: Guohua
authors: G
authors: Wang
authors: Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MA, USA. hzhu4@jhmi.edu.
authors: Heng
authors: H
authors: Zhu
authors: Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MA, USA. dzack@jhmi.edu.|Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MA, USA. dzack@jhmi.edu.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA, USA. dzack@jhmi.edu.|Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MA, USA. dzack@jhmi.edu.|Institut de la Vision, Université Pierre et Marie Curie, 17 rue Moreau, Paris, France. dzack@jhmi.edu.
authors: Donald J
authors: DJ
authors: Zack
authors: Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MA, USA. smerbs@jhmi.edu.
authors: Shannath L
authors: SL
authors: Merbs
authors: Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MA, USA. jiang.qian@jhmi.edu.
authors: Jiang
authors: J
authors: Qian
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D051379:Mice; D059372:Nucleotide Motifs / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D012160:Retina / Q000378:metabolism
chemical_list: D003850:Deoxyribonuclease I
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