A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA

Bird, Adrian; Taggart, Mary; Frommer, Marianne; Miller, Orlando J.; Macleod, Donald

doi:10.1016/0092-8674(85)90312-5

Cited by 639 publications

(383 citation statements)

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“…In accordance with the well established notion that the vast majority of CGIs are unmethylated (8), most of the (9,085 or 87.6%) CA CGIs fell within the unmethylated class and accordingly, the overall median CA CGI log 2 r/g was -2.4. In contrast, the hypermethylated CGIs were a minority (151 or 1.4%) in this group.…”

Section: Cgi Methylation Status In Cas Andmentioning

confidence: 48%

“…We therefore conducted an array-based analysis of the DNA methylation status of CpG islands (CGIs) in control (CAs) and atherosclerotic arteries (AAs). CGIs are discrete sequences present both in intra-and intergenic regions, including the promoters of about half of the human genes (8). The observation that promoter CGI hypermethylation is usually associated with gene silencing in a number of physiological situations including cancer, suggests the pivotal role of CGI DNA methylation in transcription regulation (9).…”

Section: Introductionmentioning

confidence: 99%

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Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

Castillo-Díaz

Garay-Sevilla²,

Hernández-González³

et al. 2010

Int J Mol Med

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Abstract. Global DNA hypomethylation potentially leading to pro-atherogenic gene expression occurs in atherosclerotic lesions. However, limited information is available on the genomic location of hypomethylated sequences. We present a microarray-based survey of the methylation status of CpG islands (CGIs) in 45 human atherosclerotic arteries and 16 controls. Data from 10,367 CGIs revealed that a subset (151 or 1.4%) of these was hypermethylated in control arteries. The vast majority (142 or 94%) of this CGI subset was found to be unmethylated or partially methylated in atherosclerotic tissue, while only 17 of the normally unmethylated CGIs were hypermethylated in the diseased tissue. The most common functional classes among annotated genes adjacent to or containing differentially methylated CGIs, were transcription (23%) and signalling factors (16%). The former included HOX members, PROX1, NOTCH1 and FOXP1, which are known to regulate key steps of atherogenesis. Expression analysis revealed differential expression of all CGI-associated genes analysed. Sequence analysis identified novel DNA motifs with regulatory potential, associated with differentially methylated CGIs. This study is the first large-scale analysis of DNA methylation in atherosclerosis. Our data suggest that aberrant DNA methylation in atherosclerosis affects the transcription of critical regulatory genes for the induction of a pro-atherogenic cellular phenotype.

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Section: Cgi Methylation Status In Cas Andmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

Castillo-Díaz

Garay-Sevilla²,

Hernández-González³

et al. 2010

Int J Mol Med

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“…CpG islands (CGIs) have been identified as CpG-rich regions that are associated with ∼50% of the promoter regions in the mouse genome (Bird et al 1985;GardinerGarden and Frommer 1987). Previous genome-wide DNA methylation analyses, focusing on CGIs, have indicated that every cell and tissue type has a unique DNA methylation profile, comprising at least hundreds of T-DMRs (Ohgane et al 1998;Shiota et al 2002;Strichman-Almashanu et al 2002), and these data suggested that a methylation profile could be used to identify cell types (Shiota 2004).…”

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confidence: 99%

DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression

et al. 2008

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DNA methylation constitutes an important epigenetic regulation mechanism in many eukaryotes, although the extent of DNA methylation in the regulation of gene expression in the mammalian genome is poorly understood. We developed D-REAM, a genome-wide DNA methylation analysis method for tissue-dependent and differentially methylated region (T-DMR) profiling with restriction tag-mediated amplification in mouse tissues and cells. Using a mouse promoter tiling array covering a region from −6 to 2.5 kb (∼30,000 transcription start sites), we found that over 3000 T-DMRs are hypomethylated in liver compared to cerebrum. The DNA methylation profile of liver was distinct from that of kidney and spleen. This hypomethylation profile marked genes that are specifically expressed in liver, including key transcription factors such as Hnf1a and Hnf4a. Genes with T-DMRs, especially those lacking CpG islands and those with HNF-1A binding motifis in their promoters, showed good correlation between their tissue-specific expression and liver hypomethylation status. T-DMRs located downstream from their transcription start sites also showed tissue-specific gene expression. These data indicate that multilayered regulation of tissue-specific gene function could be elucidated by DNA methylation tissue profiling.

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“…This is because of the better possibility of projecting the phenotypic impact of mutation in DNA ofknown function, a necessary objective in interpreting the significance of an increased mutation rate to a concerned public. Not I sites are disproportionately frequent in the unmethylated "CpG islands" so common at the 5' end of genes (12)(13)(14)(15)(16)(17). Thus, the use of Not I as one of the restriction fragment enzymes in the first dimension of these gels may result in the derivation of a very high proportion of the visualized fragments from active genes.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation detected by quantitative analysis of end-labeled genomic DNA fragments.

Asakawa¹,

Kuick²,

Neel³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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The continuing efforts to evaluate specific human populations for altered germinal mutation rates would profit from more efficient and more specific approaches than those of the past. To this end, we have explored the potential usefulness oftwo-dimensional electrophoresis ofDNA fragments obtained from restriction-enzyme-digested genomic DNA. This permits the analysis, on a single preparation, of -2000 DNA fragments varying in size from 1.0 to 5.0 kb in the first dimension and from 0.3 to 2.0 kb in the second dimension. To enter into a genetic analysis, these fragments must exhibit positional and quantitative stability. With respect to the latter, if spots that are the product of two homologous DNA fragments are to be distnguished with the requisite accuracy from spots that are the product of only one fragment, the coefficient of variation of spot intensity should be approximately -0.12. At present, 482 of the spots in our preparations meet these standards. In an examination of preparations based on three Japanese mother/father/child trios, 43 of these 482 spots were found to exhibit variation that segregated within families according to Mendelian principles. We have established the feasibility of cloning a variant fragment from such gels and establishing its nucleotide sequence. This technology should be highly efficient in monitoring for mutations resulting in loss/pin/rearrangement events in DNA fragments distributed throughout the genome.Research conducted in recent years has revealed a staggering wealth of genetic variation in the DNA of humans and other animals. Better techniques for the rapid identification and genetic analysis of this variation and for determining the frequency of germinal and somatic mutation, including the alterations in DNA associated with oncogenesis, are highly desirable. The advent of two-dimensional separations of genomic DNA fragments may be an important advance in this context (1)(2)(3)(4)(5). In this communication employing the technique of end-labeled restriction landmarks, we will describe the implementation of an approach for the quantitative analysis of the human DNA fragments visualized in autoradiographs of sheet gels prepared using two-dimensional electrophoresis. Elsewhere, we describe the qualitative variation detected with this technology (R.K., J.A., J.V.N., C.S., and S.M.H., unpublished data). Here, we emphasize the ability to distinguish between the autoradiographic intensity of a spot that is the product of two homologous DNA fragments as contrasted with the intensity of a fragment corresponding to one copy of the same DNA fragment. The ability to make this distinction with high accuracy provides the basis for employing this technique in the study of the frequency of mutation. Finally, we will consider the sources of nongenetic variation in spot density and discuss how the detection of genetic variation in gels of this type might be improved. MATERIALS AND METHODSDNA Samples. The DNA analyzed was obtained from three father/mother/one-child family constellat...

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A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA

Cited by 639 publications

References 33 publications

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression

Genetic variation detected by quantitative analysis of end-labeled genomic DNA fragments.

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