Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression

Abstract

Early studies proposed that DNA methylation could have a role in regulating gene expression during development [Riggs, A.D. (1975) Cytogenet. Cell Genet. 14, 9 -25]. However, some studies of DNA methylation in known tissue-specific genes during development do not support a major role for DNA methylation. In the results presented here, tissue-specific differentially methylated regions (TDMs) were first identified, and then expression of genes associated with these regions correlated with methylation status. Restriction landmark genomic scanning (RLGS) was used in conjunction with virtual RLGS to identify 150 TDMs [Matsuyama, T., Kimura, M.T., Koike, K., Abe, T., Nakao, T., Asami, T., Ebisuzaki, T., here is a history of inverse correlation between DNA methylation of CpG island promoter regions and gene expression. Almost all CpG islands on the inactive X chromosome are methylated, and monoallelic methylation of imprinted genes is associated with monoallelic gene expression (1-3). Moreover, programmed changes in DNA methylation are essential features of development, with disruption frequently resulting in aberrant development (4). Although early studies proposed that DNA methylation could have a role in regulating development (5, 6), more recent studies of DNA methylation in known tissue-specific genes during development did not support a major role for DNA methylation. Studies by Warnecke and Clark (7) found that the tissue-specific expression of the skeletal ␣-actin gene in the adult mouse does not correlate with the methylation state of the promoter. Walsh and Bestor (8) investigated the 5Ј methylation status of seven tissue-specific genes and found no correlation with tissue-specific expression. In the study presented here, rather than examining the methylation status of known tissuespecific genes, tissue-specific differentially methylated regions (TDMs) were first identified, and then genes located near the TDMs were analyzed for tissue-specific expression.Restriction landmark genomic scanning (RLGS) is a method for the two-dimensional display of end-labeled DNA restriction fragments (9-11) and can be used to scan for genomic DNA methylation (11). Because the NotI recognition site contains two CpGs and the great majority of NotI sites are within CpG islands, RLGS (with NotI as the restriction landmark) displays CpG islands and adjacent regions. If a NotI site is methylated, it will not be digested and will not be end-labeled, resulting in the absence of the spot in the RLGS profile. Global analysis of genomic DNA methylation of different tissues by using RLGS indicates that there are a relatively large number of differences in profiles suggesting TDMs (12-14). Numerous differences in the RLGS profiles of ES cells and differentiated tissues, such as kidney and brain, have been identified (13), but the DNA sequence of these genomic regions was not established, and it is not known whether these methylation differences are associated with tissue-specific gene expression.In the results presented here, RLGS was us...

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Dynamic and reversibility of heterochromatic gene silencing in human disease

“…Recent results, mostly obtained by genome wide approaches to study DNA methylation, do confirm a role for DNA methylation in tissue specific gene expression. One of these genome wide approaches known as Restriction Landmark Genome Scanning (RLGS) has enabled to identify in six mice tissues a large number of differentially methylated regions (TDMs) which exhibit a tissue-specific expression pattern that is consistent with methylation status and a role in tissue differentiation [50]. Furthermore, Ching et al [51], by using BAC microarray have identified CpG island loci that are methylated in a tissue-specific manner in normal human tissues, including SHANK3 whose differential methylation in different tissues was also evolutionary conserved.…”

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

“…DNA is methylated at a cysteine base pair, most often at a CpG dinucleotide (CpG site) 9. Methylation of CpG sites in the promoter region of a gene is commonly associated with repression of gene expression 10, 11, 12. DNA methylation occurs through the activity of DNA methyltransferases (DNMTs), particularly DNMT1 postdevelopment 13, 14, 15.…”