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

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Abstract

{BackgroundDNA} 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.ResultsBy} 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.ConclusionsWe} 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.

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Wan, J., Oliver, V. F., Wang, G., Zhu, H., Zack, D. J., Merbs, S. L., & Qian, J. (2015). Characterization of tissue-specific differential DNA methylation suggests distinct modes of positive and negative gene expression regulation. BMC Genomics, 16(1). https://doi.org/10.1186/s12864-015-1271-4

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