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Polymerase chain reaction-aided genomic sequencing of an X chromosome-linked CpG island: methylation patterns suggest clonal inheritance, CpG site autonomy, and an explanation of activity state stability. 总被引:21,自引:3,他引:21
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G P Pfeifer S D Steigerwald R S Hansen S M Gartler A D Riggs 《Proceedings of the National Academy of Sciences of the United States of America》1990,87(21):8252-8256
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McGill BE Bundle SF Yaylaoglu MB Carson JP Thaller C Zoghbi HY 《Proceedings of the National Academy of Sciences of the United States of America》2006,103(48):18267-18272
Rett syndrome (RTT), a postnatal neurodevelopmental disorder, is caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Children with RTT display cognitive and motor abnormalities as well as autistic features. We studied mice bearing a truncated Mecp2 allele (Mecp2(308/Y) mice) and found evidence of increased anxiety-like behavior and an abnormal stress response as evidenced by elevated serum corticosterone levels. We found increased corticotropin-releasing hormone (Crh) gene expression in the paraventricular nucleus of the hypothalamus, the central amygdala, and the bed nucleus of the stria terminalis. Finally, we discovered that MeCP2 binds the Crh promoter, which is enriched for methylated CpG dinucleotides. In contrast, the MeCP2(308) protein was not detected at the Crh promoter. This study identifies Crh as a target of MeCP2 and implicates Crh overexpression in the development of specific features of the Mecp2(308/Y) mouse, thereby providing opportunities for clinical investigation and therapeutic intervention in RTT. 相似文献
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Hehuang Xie Min Wang Maria de F. Bonaldo Veena Rajaram Wendy Stellpflug Christina Smith Kelly Arndt Stewart Goldman Tadanori Tomita Marcelo B. Soares 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(15):6952-6957
Global loss of DNA methylation has been known for decades as an epigenomic aberration associated with carcinogenesis and cancer progression. Loss of DNA methylation affects predominantly repetitive elements, which encompass >50% of the CpG dinucleotides present in the human genome. Because of the lack of an effective approach, no studies have been conducted to reveal such genome-wide methylation changes at a single-base resolution. To precisely determine the CpG sites with methylation loss during progression of pediatric intracranial ependymomas, we exploited a high-throughput bisulfite sequencing approach that simultaneously generates methylation profiles for thousands of Alu elements and their flanking sequences. Comparison of the methylation profiles of normal and tumor tissues revealed that the methylation status of the majority of CpG sites adjacent to or within Alu repeats remain unaltered, while a small set of CpG sites gain or lose methylation in ependymomas. Compared to the CpG sites with stable methylation level between normal control and ependymomas, the differentially methylated CpG sites are enriched in the sequences with low CpG density in the flanking regions of Alu repeats, rather than within the Alu sequences themselves. In addition, the CpG sites that are hypermethylated in ependymomas are proximal to CpG islands, whereas those that are hypomethylated are overrepresented in intergenic regions. Lastly, aberrant methylation of several genomic loci was confirmed to be associated with the aggressive primary tumors and the relapsed ependymomas. 相似文献
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De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. 总被引:10,自引:7,他引:10
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P A Jones M J Wolkowicz W M Rideout rd F A Gonzales C M Marziasz G A Coetzee S J Tapscott 《Proceedings of the National Academy of Sciences of the United States of America》1990,87(16):6117-6121
CpG dinucleotides are unevenly distributed in the vertebrate genome. Bulk DNA is depleted of CpGs and most of the cytosines in the dinucleotide in this fraction are methylated. On the other hand, CpG islands, which are often associated with genes, are unmethylated at testable sites in all normal tissues with the exception of genes on the inactive X chromosome. We used Hpa II/Msp I analysis and ligation-mediated polymerase chain reaction to examine the methylation of the MyoD1 CpG island in adult mouse tissues, early cultures of mouse embryo cells, and immortal fibroblastic cell lines. The island was almost devoid of methylation at CCGG sites in adult mouse tissues and in low-passage mouse embryo fibroblasts. In marked contrast, the island was methylated in 10T 1/2 cells and in six other immortal cell lines showing that methylation of this CpG island had occurred during escape from senescence. The island became even more methylated in chemically transformed derivatives of 10T 1/2 cells. Thus, CpG islands not methylated in normal tissues may become modified to an abnormally high degree during immortalization and transformation. 相似文献
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Genomic sequencing and in vivo footprinting of an expression-specific DNase I-hypersensitive site of avian vitellogenin II promoter reveal a demethylation of a mCpG and a change in specific interactions of proteins with DNA. 总被引:11,自引:6,他引:11
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H P Saluz I M Feavers J Jiricny J P Jost 《Proceedings of the National Academy of Sciences of the United States of America》1988,85(18):6697-6700
Genomic sequencing was used to study the in vivo methylation pattern of two CpG sites in the promoter region of the avian vitellogenin gene. The CpG at position +10 was fully methylated in DNA isolated from tissues that do not express the gene but was unmethylated in the liver of mature hens and estradiol-treated roosters. In the latter tissue, this site became demethylated and DNase I hypersensitive after estradiol treatment. A second CpG (position -52) was unmethylated in all tissues examined. In vivo genomic footprinting with dimethyl sulfate revealed different patterns of DNA protection in silent and expressed genes. In rooster liver cells, at least 10 base pairs of DNA, including the methylated CpG, were protected by protein(s). Gel-shift assays indicated that a protein factor, present in rooster liver nuclear extract, bound at this site only when it was methylated. In hen liver cells, the same unmethylated CpG lies within a protected region of approximately equal to 20 base pairs. In vitro DNase I protection and gel-shift assays indicate that this sequence is bound by a protein, which binds both double- and single-stranded DNA. For the latter substrate, this factor was shown to bind solely the noncoding (i.e., mRNA-like) strand. 相似文献
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T Naveh-Many H Cedar 《Proceedings of the National Academy of Sciences of the United States of America》1981,78(7):4246-4250
The degree of methylation of active regions of the chromosome has been investigated by several techniques. DNase I (deoxyribonuclease I, EC 3.1.21.1) was used to introduce nicks in the active regions of the nucleus and thereby specifically label these areas. By using the methylation-specific restriction enzymes Hpa II and Hha I it could be shown that active genes are more sensitive to these probes than are other parts of the genome. In order to measure the amount of methylation at all CpG residues, DNA was nick-translated in the presence of [alpha-32P]dGTP as the sole nucleotide source and the methylated cytosine was detected by the standard nearest-neighbor analysis. Using this assay, we found that about 70% of all CpG sequences in animal cell DNA are methylated. In active nuclear regions that are sensitive to DNase I, only 30-40% of the CpG residues are methylated. This method was also employed to study the gene sequences that are complementary to cellular RNA. By this criterion expressed gene sequences are only 20-30% methylated. These data suggest that undermethylation is a general phenomenon in all actively transcribed genes. 相似文献
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《Digestive and liver disease》2022,54(4):521-528
BackgroundOptimal non-invasive biomarkers for diagnosis and treatment of nonalcoholic fatty liver disease (NAFLD) remain to be identified.AimsTo identify potential DNA methylation biomarkers for NAFLD.MethodsGenome-wide DNA methylation profiling was performed to identify differentially methylated CpG sites in peripheral blood leukocytes. Differentially methylated regions were validated using the MassCLEAVE assay. The expression levels of candidate genes were explored by Gene Expression Omnibus database.ResultsThe hypomethylation of PRKCE CpG 4.5 and CpG 18.19 was associated with nonalcoholic fatty liver (NAFL), the odds ratio (OR) and 95% confidence interval (CI) were 0.129 (0.026–0.639) and 0.231 (0.069–0.768). The methylation level of CpG 1.2 and average methylation level of SEC14L3 were correlated with NAFL, with OR (95% CI) being 0.283 (0.093–0.865) and 0.264 (0.087–0.799). PRKCE CpG 4.5 and cg17802464 of SEC14L3 were correlated with body mass index, waist circumference, total triglyceride, high-density lipoprotein cholesterol, alanine aminotransferase and aspartate aminotransferase. All selected datasets showed high expression levels of PRKCE and SEC14L3 in patients with NAFLD.ConclusionsOur findings suggest that the hypomethylation of PRKCE and SEC14L3 promoters represent attractive biomarkers for NAFLD. Further studies are warranted to validate these biomarkers as molecular tools for diagnosis of NAFLD and therapeutic targets. 相似文献