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Shannath L Merbs, Jun Wan, Guohua Wang, Heng Zhu, Donald J Zack, Jiang Qian; Distinct Modes of Positive and Negative Gene Expression Regulation by Tissue-specific Differential DNA Methylation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5504.
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© ARVO (1962-2015); The Authors (2016-present)
Epigenetic modifications, like DNA methylation, are important regulators of tissue differentiation during development. Although it is well-established that promoter methylation is inversely correlated with gene expression, the role of intragenic methylation is still unclear. To better understand the function of tissue-specific differentially methylated regions (T-DMRs), we characterized tissue-specific DNA methylation between mouse retina and brain and compared the T-DMRs with tissue-specific gene expression.
DNA methylation profiling of two adult mouse tissues, retina and brain, was conducted using comprehensive high-throughput array for relative methylation (CHARM) tiling array identifying 2,498 T-DMRs. Methylation differences were correlated with expression differences from a previous study. T-DMRs were divided into 2 groups: negative and positive, based on the correlation of DNA methylation with gene expression. T-DMRs were compared to DNA hypersensitivity sites and gene ontology analysis was performed on genes associated with T-DMRs. DNA motifs associated with the T-DMRs were predicted.
As expected, the majority (66%) of the T-DMRs associated with genes were negatively correlated with gene expression; however, methylation of the remaining 34% of T-DMRs was positively correlated with gene expression. A large majority (83%) of T-DMRs were located at tissue-specific DNA hypersensitivity sites suggesting that T-DMRs are likely to play a role in tissue-specific gene regulation. 15% of the positive T-DMRs were located upstream of the transcription start site compared to 10% of the negative T-DMRs. Gene ontology analysis revealed that transcriptional repressors were more likely to be regulated by positive T-DMRs. Motif analysis revealed that distinct sets of DNA motifs were associated with positive and negative gene regulation.
CpG methylation has been thought to inhibit gene expression by disrupting transcription factor-DNA interactions directly or by recruiting methyl CpG-binding domain proteins that compete for the binding sites. Consistent with this inhibitory role for DNA methylation, the majority of tissue-specific genes appeared to be directly inhibited by DNA methylation. However our finding of positive T-DMRs associated with transcriptional repressors suggests a new two-layer mode of tissue-specific epigenetic regulation by positive T-DMRs.
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