Journal articles on the topic 'CpG Islands'
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Weitzman, Jonathan B. "CpG islands." Genome Biology 3 (2002): spotlight—20020319–01. http://dx.doi.org/10.1186/gb-spotlight-20020319-01.
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Gebhard, Claudia, Mohammed Sadeh, Dagmar Glatz, Lucia Schwarzfischer, Rainer Spang, Gerhard Ehninger, Christian Thiede, Reinhard Andreesen, and Michael Rehli. "Profiling of Aberrant DNA Methylation In AML Reveals Subclasses of CpG Islands with Epigenetic or Genetic Association." Blood 116, no. 21 (November 19, 2010): 2498. http://dx.doi.org/10.1182/blood.v116.21.2498.2498.
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Abstract Abstract 2498 CpG islands show frequent and often disease-specific epigenetic alterations during malignant transformation, however, the underlying mechanisms are poorly understood. We used methyl-CpG immunoprecipitation (MCIp) to generate comparative DNA methylation profiles of 30 patients with acute myeloid leukemia for human CpG islands across the genome. DNA methylation profiles across 23.000 CpG islands revealed highly heterogeneous methylation patterns in AML with over 6000 CpG islands showing aberrant de novo methylation in AML. Based on these profiles we selected a subset of 380 CpG islands (covering 15.000 individual CpGs) for detailed fine-mapping analyses of aberrant DNA methylation in 185 patients with AML (50% normal karyotype). We found that a proportion of patients (5/185) displayed a concerted hypermethylation at almost all studied loci, representing the rare CpG island methylator phenotype (CIMP) in AML. Meta analysis of methylation profiling and published ChIP sequencing data separated CpG islands in two groups. A highly correlated subgroup of CpG island regions was strongly associated with histone H3 lysine 27 trimethylation in human hematopoietic progenitor cells, suggesting that disease-related de novo DNA methylation at these CpG islands is linked with polycomb group protein (PcG)-mediated repression. The group of mainly non-PcG target CpG islands showed heterogeneous methylation patterns across patients and unsupervised hierarchical clustering revealed a correlation of methylation profiles with genetic disease markers, including oncofusion proteins as well as CEBPA- and NPM1-mutations. Our study suggests that both epigenetic as well as genetic aberrations may underlay AML-related changes in CpG island DNA methylation states. Disclosures: No relevant conflicts of interest to declare.
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Bender, Christina M., Mark L. Gonzalgo, Felicidad A. Gonzales, Carvell T. Nguyen, Keith D. Robertson, and Peter A. Jones. "Roles of Cell Division and Gene Transcription in the Methylation of CpG Islands." Molecular and Cellular Biology 19, no. 10 (October 1, 1999): 6690–98. http://dx.doi.org/10.1128/mcb.19.10.6690.
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ABSTRACT De novo methylation of CpG islands within the promoters of eukaryotic genes is often associated with their transcriptional repression, yet the methylation of CpG islands located downstream of promoters does not block transcription. We investigated the kinetics of mRNA induction, demethylation, and remethylation of the p16promoter and second-exon CpG islands in T24 cells after 5-aza-2′-deoxycytidine (5-Aza-CdR) treatment to explore the relationship between CpG island methylation and gene transcription. The rates of remethylation of both CpG islands were associated with time but not with the rate of cell division, and remethylation of thep16 exon 2 CpG island occurred at a higher rate than that of the p16 promoter. We also examined the relationship between the remethylation of coding sequence CpG islands and gene transcription. The kinetics of remethylation of the p16exon 2, PAX-6 exon 5, c-ABL exon 11, andMYF-3 exon 3 loci were examined following 5-Aza-CdR treatment because these genes contain exonic CpG islands which are hypermethylated in T24 cells. Remethylation occurred most rapidly in the p16, PAX-6, and c-ABL genes, shown to be transcribed prior to drug treatment. These regions also exhibited higher levels of remethylation in single-cell clones and subclones derived from 5-Aza-CdR-treated T24 cells. Our data suggest that de novo methylation is not restricted to the S phase of the cell cycle and that transcription through CpG islands does not inhibit their remethylation.
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Du, Xin, Leng Han, An-Yuan Guo, and Zhongming Zhao. "Features of Methylation and Gene Expression in the Promoter-Associated CpG Islands Using Human Methylome Data." Comparative and Functional Genomics 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/598987.
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CpG islands are typically located in the 5′end of genes and considered as gene markers because they play important roles in gene regulation via epigenetic change. In this study, we compared the features of CpG islands identified by several major algorithms by setting the parameter cutoff values in order to obtain a similar number of CpG islands in a genome. This approach allows us to systematically compare the methylation and gene expression patterns in the identified CpG islands. We found that Takai and Jones’ algorithm tends to identify longer CpG islands but with weaker CpG island features (e.g., lower GC content and lower ratio of the observed over expected CpGs) and higher methylation level. Conversely, the CpG clusters identified by Hackenberg et al.’s algorithm using stringent criteria are shorter and have stronger features and lower methylation level. In addition, we used the genome-wide base-resolution methylation profile in two cell lines to show that genes with a lower methylation level at the promoter-associated CpG islands tend to express in more tissues and have stronger expression. Our results validated that the DNA methylation of promoter-associated CpG islands suppresses gene expression at the genome level.
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Qu, Ying, Andreas Lennartsson, Verena I. Gaidzik, Stefan Deneberg, Sofia Bengtzén, Mohsen Karimi Arzenani, Lars Bullinger, Konstanze Döhner, and Sören Lehmann. "Genome-Wide DNA Methylation Analysis Shows Enrichment of Differential Methylation in “Open Seas” and Enhancers and Reveals Hypomethylation in DNMT3A Mutated Cytogenetically Normal AML (CN-AML)." Blood 120, no. 21 (November 16, 2012): 653. http://dx.doi.org/10.1182/blood.v120.21.653.653.
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Abstract Abstract 653 DNA methylation is involved in multiple biologic processes including normal cell differentiation and tumorigenesis. In AML, methylation patterns have been shown to differ significantly from normal hematopoietic cells. Most studies of DNA methylation in AML have previously focused on CpG islands within the promoter of genes, representing only a very small proportion of the DNA methylome. In this study, we performed genome-wide methylation analysis of 62 AML patients with CN-AML and CD34 positive cells from healthy controls by Illumina HumanMethylation450K Array covering 450.000 CpG sites in CpG islands as well as genomic regions far from CpG islands. Differentially methylated CpG sites (DMS) between CN-AML and normal hematopoietic cells were calculated and the most significant enrichment of DMS was found in regions more than 4kb from CpG Islands, in the so called open sea where hypomethylation was the dominant form of aberrant methylation. In contrast, CpG islands were not enriched for DMS and DMS in CpG islands were dominated by hypermethylation. DMS successively further away from CpG islands in CpG island shores (up to 2kb from CpG Island) and shelves (from 2kb to 4kb from Island) showed increasing degree of hypomethylation in AML cells. Among regions defined by their relation to gene structures, CpG dinucleotide located in theoretic enhancers were found to be the most enriched for DMS (Chi χ2<0.0001) with the majority of DMS showing decreased methylation compared to CD34 normal controls. To address the relation to gene expression, GEP (gene expression profiling) by microarray was carried out on 32 of the CN-AML patients. Totally, 339723 CpG sites covering 18879 genes were addressed on both platforms. CpG methylation in CpG islands showed the most pronounced anti-correlation (spearman ρ =-0.4145) with gene expression level, followed by CpG island shores (mean spearman rho for both sides' shore ρ=-0.2350). As transcription factors (TFs) have shown to be crucial for AML development, we especially studied differential methylation of an unbiased selection of 1638 TFs. The most enriched differential methylation between CN-AML and normal CD34 positive cells were found in TFs known to be involved in hematopoiesis and with Wilms tumor protein-1 (WT1), activator protein 1 (AP-1) and runt-related transcription factor 1 (RUNX1) being the most differentially methylated TFs. The differential methylation in WT 1 and RUNX1 was located in intragenic regions which were confirmed by pyro-sequencing. AML cases were characterized with respect to mutations in FLT3, NPM1, IDH1, IDH2 and DNMT3A. Correlation analysis between genome wide methylation patterns and mutational status showed statistically significant hypomethylation of CpG Island (p<0.0001) and to a lesser extent CpG island shores (p<0.001) and the presence of DNMT3A mutations. This links DNMT3A mutations for the first time to a hypomethylated phenotype. Further analyses correlating methylation patterns to other clinical data such as clinical outcome are ongoing. In conclusion, our study revealed that non-CpG island regions and in particular enhancers are the most aberrantly methylated genomic regions in AML and that WT 1 and RUNX1 are the most differentially methylated TFs. Furthermore, our data suggests a hypomethylated phenotype in DNMT3A mutated AML. Disclosures: No relevant conflicts of interest to declare.
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Kim, Ki-Bong. "CpG Islands Detector: a Window-based CpG Island Search Tool." Genomics & Informatics 8, no. 1 (March 31, 2010): 58–61. http://dx.doi.org/10.5808/gi.2010.8.1.058.
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Macleod, Donald, Robin R. Ali, and Adrian Bird. "An Alternative Promoter in the Mouse Major Histocompatibility Complex Class II I-Aβ Gene: Implications for the Origin of CpG Islands." Molecular and Cellular Biology 18, no. 8 (August 1, 1998): 4433–43. http://dx.doi.org/10.1128/mcb.18.8.4433.
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ABSTRACT Nonmethylated CpG islands are generally located at the 5′ ends of genes, but a CpG island in the mouse major histocompatibility complex class II I-Aβ gene is remote from the promoter and covers exon 2. We have found that this CpG island includes a novel intronic promoter that is active in embryonic and germ cells. The resulting transcript potentially encodes a severely truncated protein which would lack the signal peptide and external β1 domains. The functional significance of the internal CpG island may be to facilitate gene conversion, thereby sustaining the high level of polymorphism seen at exon 2. Deletions of the I-Aβ CpG island promoter reduce transcription and frequently lead to methylation of the CpG island in a transgenic mouse assay. These and other results support the idea that all CpG islands arise at promoters that are active in early embryonic cells.
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Rizwana, R., and P. J. Hahn. "CpG methylation reduces genomic instability." Journal of Cell Science 112, no. 24 (December 15, 1999): 4513–19. http://dx.doi.org/10.1242/jcs.112.24.4513.
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Hypomethylation of DNA in tumor cells is associated with genomic instability and has been suggested to be due to activation of mitotic recombination. We have studied the methylation patterns in two 650 kb double minute chromosomes present in two mouse tumor cell lines, resistant to methotrexate. Multiple copies of the double minute chromosomes amplifying the dihydrofolate reductase gene are present in both the cell lines. In one of the cell lines (Mut F), two unmethylated CpG islands in the double minute chromosomes are readily cleaved by methylation-sensitive rare-cutting restriction endonucleases. In the other cell line (Mut C), the cleavage sites in the double minute chromosomes are partially methylated and resistant to cleavage. The double minute chromosomes with the two unmethylated CpG islands undergo rapid dimerization, whereas the double minute chromosomes with the partially methylated CpG islands are unchanged in size for over a year in continuous culture. The partially methylated CpG islands can be demethylated by azacytidine treatment or naturally by extended time in culture, and become sensitive to cleavage with the rare-cutting restriction endonucleases. The Mut C double minute chromosomes, with the newly demethylated CpG islands, but not the double minute chromosomes with the partially methylated CpG islands, undergo deletions and dimerizations. These results suggest a role for CpG island methylation controlling mitotic recombination between and within large DNA molecules.
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Aoto, Saki, Mayu Fushimi, Kei Yura, and Kohji Okamura. "Diversification of CpG-Island Promoters Revealed by Comparative Analysis Between Human and Rhesus Monkey Genomes." Mammalian Genome 31, no. 7-8 (July 9, 2020): 240–51. http://dx.doi.org/10.1007/s00335-020-09844-2.
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Abstract While CpG dinucleotides are significantly reduced compared to other dinucleotides in mammalian genomes, they can congregate and form CpG islands, which localize around the 5ʹ regions of genes, where they function as promoters. CpG-island promoters are generally unmethylated and are often found in housekeeping genes. However, their nucleotide sequences and existence per se are not conserved between humans and mice, which may be due to evolutionary gain and loss of the regulatory regions. In this study, human and rhesus monkey genomes, with moderately conserved sequences, were compared at base resolution. Using transcription start site data, we first validated our methods’ ability to identify orthologous promoters and indicated a limitation using the 5ʹ end of curated gene models, such as NCBI RefSeq, as their transcription start sites. We found that, in addition to deamination mutations, insertions and deletions of bases, repeats, and long fragments contributed to the mutations of CpG dinucleotides. We also observed that the G + C contents tended to change in CpG-poor environments, while CpG content was altered in G + C-rich environments. While loss of CpG islands can be caused by gradual decreases in CpG sites, gain of these islands appear to require two distinct nucleotide altering steps. Taken together, our findings provide novel insights into the process of acquisition and diversification of CpG-island promoters in vertebrates.
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Mitchell, C. M., T. Zakar, S. D. Sykes, K. G. Pringle, and E. R. Lumbers. "141. METHYLATION OF GENES OF THE RENIN ANGIOTENSIN SYSTEM (RAS) IN EARLY HUMAN AMNION." Reproduction, Fertility and Development 22, no. 9 (2010): 59. http://dx.doi.org/10.1071/srb10abs141.
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The renin angiotensin system (RAS) genes angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1) and prorenin receptor (ATP6AP2) have CpG islands at their promoters, so these genes may be regulated by CpG island methylation as may the expression of two proteases implicated in prorenin activation (cathepsin D {CTSD} and kallikrein 1 {KLK1}). We measured CpG island methylation of 3 RAS genes and of CTSD and KLK1 in amnion using the Methyl-Profiler assay (SA Biosciences), which discriminates methyl-CpG density between hypermethylated, intermediately methylated and unmethylated CpG islands. DNA from human amnion collected between 10–17.8 weeks gestation, at elective caesarean section and after labour at term was analysed. The bulk (>80%) of CpG islands in all genes examined except for KLK1 was unmethylated and without intermediate methylation throughout gestation, while the rest was hypermethylated. There was no change in methylation density with labour (Table 1). In early gestation KLK1 methylation was greater than ACE, AGTR1 and ATP6AP2 (P < 0.05). KLKI methylation shifted towards the unmethylated state after labour (P < 0.05). There were correlations between methylation of ACE, AGTR1 and ATP6AP2 (P < 0.02) but not between RAS genes and KLKI. This suggests that the 3 RAS genes in amnion are not controlled by CpG island methylation. It is likely, however, that KLK1 is silenced in early gestation amnion partially by CpG island methylation, which is reduced by term. Since Kallikrein 1 can activate prorenin, the methylation status of this gene may regulate RAS activity in amnion during gestation.
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Choi, Y. C., and C. B. Chae. "Demethylation of somatic and testis-specific histone H2A and H2B genes in F9 embryonal carcinoma cells." Molecular and Cellular Biology 13, no. 9 (September 1993): 5538–48. http://dx.doi.org/10.1128/mcb.13.9.5538-5548.1993.
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In contrast to many other genes containing a CpG island, the testis-specific H2B (TH2B) histone gene exhibits tissue-specific methylation patterns in correlation with gene activity. Characterization of the methylation patterns within a 20-kb segment containing the TH2A and TH2B genes in comparison with that in a somatic histone cluster revealed that: (i) the germ cell-specific unmethylated domain of the TH2A and TH2B genes is defined as a small region surrounding the CpG islands of the TH2A and TH2B genes and (ii) somatic histone genes are unmethylated in both liver and germ cells, like other genes containing CpG islands, whereas flanking sequences are methylated. Transfection of in vitro-methylated TH2B, somatic H2B, and mouse metallothionein I constructs into F9 embryonal carcinoma cells revealed that the CpG islands of the TH2A and TH2B genes were demethylated like those of the somatic H2A and H2B genes and the metallothionein I gene. The demethylation of those CpG islands became significantly inefficient at a high number of integrated copies and a high density of methylated CpG dinucleotides. In contrast, three sites in the somatic histone cluster, of which two sites are located in the long terminal repeat of an endogenous retrovirus-like sequence, were efficiently demethylated even at a high copy number and a high density of methylated CpG dinucleotides. These results suggest two possible mechanisms for demethylation in F9 cells and methylation of CpG islands of the TH2A and TH2B genes at the postblastula stage during embryogenesis.
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Choi, Y. C., and C. B. Chae. "Demethylation of somatic and testis-specific histone H2A and H2B genes in F9 embryonal carcinoma cells." Molecular and Cellular Biology 13, no. 9 (September 1993): 5538–48. http://dx.doi.org/10.1128/mcb.13.9.5538.
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In contrast to many other genes containing a CpG island, the testis-specific H2B (TH2B) histone gene exhibits tissue-specific methylation patterns in correlation with gene activity. Characterization of the methylation patterns within a 20-kb segment containing the TH2A and TH2B genes in comparison with that in a somatic histone cluster revealed that: (i) the germ cell-specific unmethylated domain of the TH2A and TH2B genes is defined as a small region surrounding the CpG islands of the TH2A and TH2B genes and (ii) somatic histone genes are unmethylated in both liver and germ cells, like other genes containing CpG islands, whereas flanking sequences are methylated. Transfection of in vitro-methylated TH2B, somatic H2B, and mouse metallothionein I constructs into F9 embryonal carcinoma cells revealed that the CpG islands of the TH2A and TH2B genes were demethylated like those of the somatic H2A and H2B genes and the metallothionein I gene. The demethylation of those CpG islands became significantly inefficient at a high number of integrated copies and a high density of methylated CpG dinucleotides. In contrast, three sites in the somatic histone cluster, of which two sites are located in the long terminal repeat of an endogenous retrovirus-like sequence, were efficiently demethylated even at a high copy number and a high density of methylated CpG dinucleotides. These results suggest two possible mechanisms for demethylation in F9 cells and methylation of CpG islands of the TH2A and TH2B genes at the postblastula stage during embryogenesis.
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AL-Eitan, Laith N., Mansour A. Alghamdi, Amneh H. Tarkhan, and Firas A. Al-Qarqaz. "Genome-Wide CpG Island Methylation Profiles of Cutaneous Skin with and without HPV Infection." International Journal of Molecular Sciences 20, no. 19 (September 28, 2019): 4822. http://dx.doi.org/10.3390/ijms20194822.
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HPV infection is one of the most commonly transmitted diseases among the global population. While it can be asymptomatic, non-genital HPV infection often gives rise to cutaneous warts, which are benign growths arising from the epidermal layer of the skin. This study aimed to produce a global analysis of the ways in which cutaneous wart formation affected the CpG island methylome. The Infinium MethylationEPIC BeadChip microarray was utilized in order to quantitatively interrogate CpG island methylation in genomic DNA extracted from 24 paired wart and normal skin samples. Differential methylation analysis was carried out by means of assigning a combined rank score using RnBeads. The 1000 top-ranking CpG islands were then subject to Locus Overlap Analysis (LOLA) for enrichment of genomic ranges, while signaling pathway analysis was carried out on the top 100 differentially methylated CpG islands. Differential methylation analysis illustrated that the most differentially methylated CpG islands in warts lay within the ITGB5, DTNB, RBFOX3, SLC6A9, and C2orf27A genes. In addition, the most enriched genomic region sets in warts were Sheffield’s tissue-clustered DNase hypersensitive sites, ENCODE’s segmentation and transcription factor binding sites, codex sites, and the epigenome sites from cistrome. Lastly, signaling pathway analysis showed that the GRB2, GNB1, NTRK1, AXIN1, and SKI genes were the most common regulators of the genes associated with the top 100 most differentially methylated CpG islands in warts. Our study shows that HPV-induced cutaneous warts have a clear CpG island methylation profile that sets them apart from normal skin. Such a finding could account for the temporary nature of warts and the capacity for individuals to undergo clinical remission.
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Fazzari, Melissa J., and John M. Greally. "Epigenomics: beyond CpG islands." Nature Reviews Genetics 5, no. 6 (June 2004): 446–55. http://dx.doi.org/10.1038/nrg1349.
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Cross, Sally H., and Adrian P. Bird. "CpG islands and genes." Current Opinion in Genetics & Development 5, no. 3 (June 1995): 309–14. http://dx.doi.org/10.1016/0959-437x(95)80044-1.
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Patel, S. A., D. M. Graunke, and R. O. Pieper. "Aberrant silencing of the CpG island-containing human O6-methylguanine DNA methyltransferase gene is associated with the loss of nucleosome-like positioning." Molecular and Cellular Biology 17, no. 10 (October 1997): 5813–22. http://dx.doi.org/10.1128/mcb.17.10.5813.
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Tumor-associated aberrant silencing of CpG island-containing genes has been correlated with increased cytosine methylation, a "closed" chromatin structure, and exclusion of transcription factor binding in the CpG island/promoter regions of affected genes. Given the lack of understanding of what constitutes a closed chromatin structure in CpG islands, however, it has been difficult to assess the relationship among cytosine methylation, chromatin structure, and inappropriate gene silencing. In this study, nuclease accessibility analysis was used to more clearly define the chromatin structure in the CpG island of the human O6-methylguanine DNA methyltransferase (MGMT) gene. Chromatin structure was then related to in vivo DNA-protein interactions and cytosine methylation status of the MGMT CpG island in human glioma cells varying in MGMT expression. The results of these studies indicated that the "open" chromatin structure associated with the MGMT CpG island in MGMT+ cells consisted of an approximately 250-bp transcription factor-binding, nuclease-accessible, nucleosome-free region of DNA, whose formation was associated with at least four flanking, precisely positioned nucleosome-like structures. In MGMT- cells, this precise nucleosomal array was lost and was replaced by randomly positioned nucleosomes (i.e., the closed chromatin structure), regardless of whether methylation of the CpG island was spread over the entire island or limited to regions outside the transcription factor binding region. These results suggest that CpG islands facilitate the expression of housekeeping genes by facilitating nucleosomal positioning and that the conditions that alter the formation of this array (such as perhaps methylation) may indirectly affect CpG island-containing gene expression.
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Jelinek, Jaroslav, Rajan Mannari, and Jean-Pierre Issa. "Identification of 41 Novel Promoter-Associated CpG Islands Methylated in Leukemias." Blood 104, no. 11 (November 16, 2004): 1126. http://dx.doi.org/10.1182/blood.v104.11.1126.1126.
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Abstract DNA methylation within promoter-associated CpG islands is a well-recognized mechanism of gene silencing and plays an important role in the development of malignancies. CpG dinucleotides in human DNA are methylated at 5′-cytosine with the exception of areas with dense concentration of CpGs (CpG islands) located in gene promoter regions. In cancer cells, methylation of CpG islands in promoter regions of tumor suppressor genes is a frequent epigenetic change with a gene-silencing effect analogous to inactivating mutations. Methylation profiling can identify biologically and clinically distinct tumor subgroups by mapping the methylation status of multiple genes, and reports in AML and ALL suggest associations between methylation and poor prognosis. Identification of methylated CpG islands can shed new light on the biology of leukemia. We used Methylated CpG Island Amplification coupled with Representative Difference Analysis (MCA-RDA) as a genome-wide screen for promoter-associated CpG islands methylated in leukemic and/or myeloproliferative cell lines and primary malignant cells, but unmethylated in blood cells from normal controls. We identified 51 unique promoter-associated CpG islands in 321 sequenced clones recovered by MCA-RDA. Forty-one CpG islands belonged to known genes, and 10 to annotated mRNAs. Of the genes with known function, 8 are involved in signaling, 7 in transcription, 3 in dephosphorylation, 2 in oxido-reductive processes, 2 in NO synthesis, 2 in adhesion, 2 in solute transport, and 2 in DNA replication. Seven out of the 51 genes were previously reported as methylated in cancer or leukemia (CDH13, HLA-B, HLA-C, PGR, SCGB3A1, SLC26A4, TERT), thus validating the MCA-RDA approach. Of the 41 new hypermethylated CpG islands recovered, 20 corresponded to genes of known function. Published data infer an association with cancer for 10 of these genes (CTDSPL, ECGF1, EDG4, FOXD2, NOR1, NOS3, OLIG2, SLC16A1, TLE1, WNT5B), and no reports were found for the other 10 genes (CNR1, FADS, FBXW3, FGD1, NPM2, P518, PDE4DIP, SNCB, TCEA3, VENTX2). To further validate our findings we are assessing the methylation status of these genes by bisulfite pyrosequencing. Analyses of the bone marrow samples from AML, ALL, CML and MDS patients are ongoing. Our preliminary data confirm methylation of H-cadherin precursor (CDH13), progesterone receptor (PGR) in AML and ALL and cannabinoid receptor 1 (CNR1) in ALL (Table). In conclusion, MCA-RDA identified methylation of 41 new and 10 previously reported promoter-associated CpG islands in leukemia. Functional studies of these may shed new light on the biology of leukemias, and these genes may be useful for methylation profiling of leukemias for prognosis and response to treatment. Promoter CpG Island Methylation Gene AML ALL Methylation levels over 10% for CDH13 and PGR and over 25% for CNR1 were scored as positive. CDH13 5/23 22% 12/19 63% PGR A Isoform 11/22 50% 12/18 67% PGR B Isoform 17/24 71% 5/13 38% CNR1 0/24 0% 3/18 17%
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McQueen, Heather A., Victoria H. Clark, Adrian P. Bird, Martine Yerle, and Alan L. Archibald. "CpG Islands of the Pig." Genome Research 7, no. 9 (September 1, 1997): 924–31. http://dx.doi.org/10.1101/gr.7.9.924.
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Illingworth, Robert S., and Adrian P. Bird. "CpG islands - ‘A rough guide’." FEBS Letters 583, no. 11 (April 17, 2009): 1713–20. http://dx.doi.org/10.1016/j.febslet.2009.04.012.
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McCarthy, Nicola. "CpG islands and 5-hydroxymethylcytosine." Nature Reviews Cancer 12, no. 6 (May 24, 2012): 374. http://dx.doi.org/10.1038/nrc3293.
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Gardiner-Garden, M., and M. Frommer. "CpG Islands in vertebrate genomes." Journal of Molecular Biology 196, no. 2 (July 1987): 261–82. http://dx.doi.org/10.1016/0022-2836(87)90689-9.
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Wei, Loo Keat, Heidi Sutherland, Anthony Au, Emily Camilleri, Larisa M. Haupt, Siew Hua Gan, and Lyn R. Griffiths. "Methylenetetrahydrofolate Reductase CpG Islands: Epigenotyping." Journal of Clinical Laboratory Analysis 30, no. 4 (June 25, 2015): 335–44. http://dx.doi.org/10.1002/jcla.21860.
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Gardiner-Garden, M., and M. Frommer. "Transcripts and CpG islands associated with the pro-opiomelanocortin gene and other neurally expressed genes." Journal of Molecular Endocrinology 12, no. 3 (June 1994): 365–82. http://dx.doi.org/10.1677/jme.0.0120365.
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ABSTRACT DNA sequences of vertebrate genes which code for neural or neuroendocrine peptides were analysed in terms of CpG dinucleotide distribution and G+C content. The vast majority of the genes were found to contain a region with the sequence characteristics of a CpG island surrounding the 5′ end. In mammalian species, the gene which codes for the neuroendocrine polypeptide pro-opiomelanocortin (POMC) was shown to be associated with two separate CpG islands: a 5′ CpG island which surrounds the POMC transcription start site and a 3′ CpG island which lies approximately 5 kb downstream, encompassing the third exon of POMC. Short POMC-related transcripts, known to be transcribed in the germline, were found to initiate from a promoter within the 3′ CpG island. The start sites of the short POMC-related transcripts in mouse testis were mapped to the region coding for γMSH in exon 3, in a similar location to transcription start sites identified in other mammalian POMC genes. Similar short POMC-related transcripts were identified in both the mouse F9 embryonal carcinoma cell line and mouse embryonic stem cells, suggesting that transcription initiating within the third exon may occur very early in development. No short transcripts were detected by Northern blot hybridization in either Xenopus laevis testis or oocyte poly(A)+ RNA extracts. The Xenopus laevis POMC genes, A and B, were associated with neither a 5′ nor a 3′ CpG island. Hence, the presence of a 5′ CpG island is not required for production of full-length transcripts from the Xenopus laevis POMC gene, but the presence of a 3′ CpG island may be required for transcription to occur from the third exon.
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Nannya, Yasuhito, Akira Hangaishi, Masashi Sanada, Lili Wang, Noriko Hosoya, Hisamaru Hirai, Mineo Kurokawa, Shigeru Chiba, and Seishi Ogawa. "Comprehensive Analysis of Methylation of CpG Islands on the Long Arm of Chromosome 7." Blood 104, no. 11 (November 16, 2004): 4341. http://dx.doi.org/10.1182/blood.v104.11.4341.4341.
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Abstract Deletion of the long arm of chromosome 7 is frequently observed in hematological malignancy and constitutes one of the most important prognostic factors. So, it is supposed that a tumor suppressing gene is located in this region, and several attempts with classical analysis methods have been executed. However, none of the genes has been identified thus far. On the other hand, methylation of the promoter region of genes is now recognized as a common mechanism of gene silencing in malignancy and frequently observed in hematological malignancy. Especially in myelodysplastic syndrome, demethylating agents such as 5-aza-2′ deoxycytidine are shown to have clinical usefulness. In order to find a gene inactivated in hematological malignancy, we comprehensively analyzed the CpG island methylation on the long arm of chromosome 7 of 5 normal blood, 13 primary leukemic bone marrow, and cell lines established from various hematological malignancies. We treated the sample genome with sodium bisulfite and directly sequenced the PCR-amplified CpG islands. Degrees of CpG island hypermethylation are widely varying in different tumors samples with much higher frequencies observed in cultured tumor cell lines. The levels of methylation are considerably varying among different samples, with higher methylation levels in cultured tumor cell lines, intermediate for primary tumor samples, and lowest in normal tissues. In contrast, however, patterns of methylation are largely similar among different samples with varying methylation levels, which creates a unique clustering pattern of methylated CpG islands, indicating some regions of the chromosome arm are more prone to methylation than others. We also examined the expression levels of DNA methyltransferases (DNMT) 1, 3a, and 3b by real-time PCR. However, there is no correlation between the expression of these genes and overall methylation level of CpG islands. We identified 25 genes that show malignancy-specific methylation. We consider that these genes are candidates of tumor suppressor genes and inquiring into deletion, methylation, and methylation analysis. We also show that methylation level of CpG islands is inversely correlated with the density of SP1 binding sequence in normal cells, which is obscured in case of primary tumors and no more observed in cultured cell lines. We also show that CpG islands that are on 5′-end of genes show lower methylation levels than those not on 5′ of genes in normal samples. Again, this trend tends to be a little lost in primary leukemia samples and further collapsed in cultured tumor cell lines, though the relation is still in a significant level. Together with previous observations, we support the hypothesis that SP1-binding sequence or active transcription protects normal CpG islands from methylation. Our observation that these phenomena disappear or diminish shows that the mechanism of aberrant methylation in malignancy is the loss of these protection mechanisms.
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Oshikawa, Daiki, Shintaro Inaba, Yudai Kitagawa, Kaori Tsukakoshi, and Kazunori Ikebukuro. "CpG Methylation Altered the Stability and Structure of the i-Motifs Located in the CpG Islands." International Journal of Molecular Sciences 23, no. 12 (June 9, 2022): 6467. http://dx.doi.org/10.3390/ijms23126467.
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Cytosine methylation within the 5′-C-phosphate-G-3′ sequence of nucleotides (called CpG methylation) is a well-known epigenetic modification of genomic DNA that plays an important role in gene expression and development. CpG methylation is likely to be altered in the CpG islands. CpG islands are rich in cytosine, forming a structure called the i-motif via cytosine-cytosine hydrogen bonding. However, little is known about the effect of CpG methylation on the i-motif. In this study, The CpG methylation-induced structural changes on the i-motif was examined by thermal stability, circular dichroism (CD) spectroscopy, and native-polyacrylamide gel electrophoresis (Native-PAGE) evaluation of five i-motif-forming DNAs from four cancer-related genes (VEGF, C-KIT, BCL2, and HRAS). This research shows that CpG methylation increased the transitional pH of several i-motif-forming DNAs and their thermal stability. When examining the effect of CpG methylation on the i-motif in the presence of opposite G4-forming DNAs, CpG methylation influenced the proportion of G4 and i-motif formation. This study showed that CpG methylation altered the stability and structure of the i-motif in CpG islands.
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Huxley, C., and M. Fried. "The mouse surfeit locus contains a cluster of six genes associated with four CpG-rich islands in 32 kilobases of genomic DNA." Molecular and Cellular Biology 10, no. 2 (February 1990): 605–14. http://dx.doi.org/10.1128/mcb.10.2.605-614.1990.
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The clustered arrangement (no two adjacent genes are separated by more than 73 base pairs [bp] and two genes overlap by 133 bp at their 3' ends) of the four genes (Surf-1 to -4) identified so far in the mouse surfeit locus (T. Williams, J. Yon, C. Huxley, and M. Fried, Proc. Natl. Acad. Sci. USA 85:3527-3530, 1988) is the tightest gene clustering found in any mammalian genome to date and strongly suggests the possibility of cis-interaction and/or coregulation of gene expression. Thus, we are analyzing the surfeit genes in detail and are defining the extent of the cluster. Here we present the sequence of the entire Surf-4 gene and define the 3' and 5' extents of its mRNAs. The Surf-4 gene has heterogeneous transcriptional start sites, and its 5' end lies in a CpG-rich island. The gene specifies three mRNAs, with the two most abundant mRNAs differing in the locations of their 3' polyadenylation sites. Only the most abundant Surf-4 mRNA would overlap the 3' end of the Surf-2 gene by 133 bp. Two new genes (Surf-5 and Surf-6) have been identified in the surfeit gene cluster by Northern (RNA) blot analysis. The 5' end of Surf-6 lies within the CpG-rich island about 8 kilobases (kb) from the CpG-rich island containing the 5' end of Surf-3, and Surf-5 lies between Surf-3 and Surf-6. Thus, the cluster contains a unique arrangement of four CpG-rich islands within 32 kb associated with the 5' ends of the six surfeit genes. The neighboring CpG-rich islands have been located 500 and 100 kb distant on either side of the surfeit cluster, indicating that the end of the cluster of islands has been reached.
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Huxley, C., and M. Fried. "The mouse surfeit locus contains a cluster of six genes associated with four CpG-rich islands in 32 kilobases of genomic DNA." Molecular and Cellular Biology 10, no. 2 (February 1990): 605–14. http://dx.doi.org/10.1128/mcb.10.2.605.
Full textAbstract:
The clustered arrangement (no two adjacent genes are separated by more than 73 base pairs [bp] and two genes overlap by 133 bp at their 3' ends) of the four genes (Surf-1 to -4) identified so far in the mouse surfeit locus (T. Williams, J. Yon, C. Huxley, and M. Fried, Proc. Natl. Acad. Sci. USA 85:3527-3530, 1988) is the tightest gene clustering found in any mammalian genome to date and strongly suggests the possibility of cis-interaction and/or coregulation of gene expression. Thus, we are analyzing the surfeit genes in detail and are defining the extent of the cluster. Here we present the sequence of the entire Surf-4 gene and define the 3' and 5' extents of its mRNAs. The Surf-4 gene has heterogeneous transcriptional start sites, and its 5' end lies in a CpG-rich island. The gene specifies three mRNAs, with the two most abundant mRNAs differing in the locations of their 3' polyadenylation sites. Only the most abundant Surf-4 mRNA would overlap the 3' end of the Surf-2 gene by 133 bp. Two new genes (Surf-5 and Surf-6) have been identified in the surfeit gene cluster by Northern (RNA) blot analysis. The 5' end of Surf-6 lies within the CpG-rich island about 8 kilobases (kb) from the CpG-rich island containing the 5' end of Surf-3, and Surf-5 lies between Surf-3 and Surf-6. Thus, the cluster contains a unique arrangement of four CpG-rich islands within 32 kb associated with the 5' ends of the six surfeit genes. The neighboring CpG-rich islands have been located 500 and 100 kb distant on either side of the surfeit cluster, indicating that the end of the cluster of islands has been reached.
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Ke, X., and A. Collins. "CpG Islands in Human X-Inactivation." Annals of Human Genetics 67, no. 3 (May 2003): 242–49. http://dx.doi.org/10.1046/j.1469-1809.2003.00038.x.
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Sarda, Shrutii, and Sridhar Hannenhalli. "Orphan CpG islands as alternative promoters." Transcription 9, no. 3 (November 28, 2017): 171–76. http://dx.doi.org/10.1080/21541264.2017.1373209.
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Carotti, Daniela, Franco Palitti, Patrizia Lavia, and Roberto Strom. "In vitromethylation of CpG-rich islands." Nucleic Acids Research 17, no. 22 (1989): 9219–29. http://dx.doi.org/10.1093/nar/17.22.9219.
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Singh, Harinder. "Teeing Up Transcription on CpG Islands." Journal of End-to-End-testing 138, no. 1 (July 10, 2009): 14–16. http://dx.doi.org/10.1016/s9999-9994(09)20374-6.
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Singh, Harinder. "Teeing Up Transcription on CpG Islands." Cell 138, no. 1 (July 2009): 14–16. http://dx.doi.org/10.1016/j.cell.2009.06.028.
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Tazi, J. "Alternative chromatin structure at CpG islands." Cell 60, no. 6 (March 23, 1990): 909–20. http://dx.doi.org/10.1016/0092-8674(90)90339-g.
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Rizwana, Rabia, and Peter J. Hahn. "CpG Islands and Double-Minute Chromosomes." Genomics 51, no. 2 (July 1998): 207–15. http://dx.doi.org/10.1006/geno.1998.5396.
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Strathdee, G., and R. Brown. "Aberrant DNA methylation in cancer: potential clinical interventions." Expert Reviews in Molecular Medicine 4, no. 4 (March 4, 2002): 1–17. http://dx.doi.org/10.1017/s1462399402004222.
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DNA methylation, the addition of a methyl group to the carbon-5 position of cytosine residues, is the only common covalent modification of human DNA and occurs almost exclusively at cytosines that are followed immediately by a guanine (so-called CpG dinucleotides). The bulk of the genome displays a clear depletion of CpG dinucleotides, and those that are present are nearly always methylated. By contrast, small stretches of DNA, known as CpG islands, are comparatively rich in CpG nucleotides and are nearly always free of methylation. These CpG islands are frequently located within the promoter regions of human genes, and methylation within the islands has been shown to be associated with transcriptional inactivation of the corresponding gene. Alterations in DNA methylation might be pivotal in the development of most cancers. In recent years, it has become apparent that the pattern of DNA methylation observed in cancer generally shows a dramatic shift compared with that of normal tissue. Although cancers often exhibit clear reductions throughout their genomes in the levels of DNA methylation, this goes hand-in-hand with increased methylation at the CpG islands. Such changes in methylation have a central role in tumourigenesis; in particular, methylation of CpG islands has been shown to be important in transcriptional repression of numerous genes that function to prevent tumour growth or development. Studies of DNA methylation in cancer have thus opened up new opportunities for diagnosis, prognosis and ultimately treatment of human tumours.
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Tong, Weigang, Shao-Qing Kuang, William Wierda, Michael J. Keating, and Guillermo Garcia-Manero. "Identification of Multiple Promoter Associated CpG Islands Commonly Methylated in Both Acute Lymphocytic Leukemia (ALL) and Chronic Lymphocytic Leukemia(CLL) Using Novel Genome-Wide Microarray Technique: Implications for Common Primordial Molecular Pathways in Lymphoid Leukemias." Blood 112, no. 11 (November 16, 2008): 2263. http://dx.doi.org/10.1182/blood.v112.11.2263.2263.
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Abstract Background: Aberrant DNA methylation of multiple promoter associated CpG islands is very prevalent phenomenon in human leukemias. Data from several laboratories indicate that methylation profiling allows the identification of leukemia patients with different prognosis. It is now accepted that human leukemias are characterized by the methylation of multiple promoter CpG islands involving multiple epigenetically dyregulated molecular pathways. Little is known in terms of the molecular epigenetic heterogeneity of different lymphoid malignancies. The identification of specific molecular pathways shared by phenotypic/genetic distinct types of leukemias may provide important understanding of critical molecular pathways in leukemia. Aims: To compare the genome-wide methylation profiles of ALL and CLL. To do so, we have used a genome wide methylation assay combining MCA (Methylated CpG island Amplification) with the Agilent promoter CpG array. This allows the identification simultaneously of hundreds of abnormally methylated CpG islands. The aim was to identify common epigenetically regulated pathways shared by both disorders. Results: We identified 280 promoter CpG islands differentially methylated in CLL and 405 protomer CpG island differentially methylated in ALL. Of all these genes, 47 (7.4%) of them were commonly methylated in both ALL and CLL. We then characterized the methylation profiles of these 47 genes in a cohort of ALL (N=24) and CLL (N=78) patient samples and tried to identify common molecular pathway(s) that are epigenetically deregulated in ALL and CLL. We also performed interaction pathway and functional analysis of these 47 genes using the online Ingenuity Pathway Analysis tools. The initial analysis divided these genes into 8 functional networks, with major functions involving cancer, cell growth and differentiation, and tissue development. We validated 18 of these 47 genes (NR2F2, SOX14, SOX11, DLX1, DLX4, FAM62C, BLC11B, KLK10, PRIMA1, HAND2, BNC1, SPOCK, COL2A, GPC6, SSTR1, PEG10, BASP1, CYP1B1) in human leukemia cell lines (N=22), CLL patient samples (N=78), ALL patient samples (N=24) and normal CD19+ B-cells (NBCs) from healthy controls (N=10). All of the 18 genes with the exception of BNC1 have higher level of methylation in leukemia cell lines, CLL and ALL patients than NBCs. For some of these genes, the level of methyation was usually higher in ALL than CLL patients (NR2F2, p=0.03; SOX14, p=0.0005; DLX4, p=0.0001; FAM62C, p=0.0003; KLK10, p=0.039; PRIMA1, p=0.0001; HAND2, p=0.0001; BNC1, p=0.003; BASP1, p=0.0001; CYP1B1, p=0.0001). Conclusions: The current study identified 47 promoter CpG islands that are commonly methylated in both ALL and CLL using MCA-microarray technique. This information will help target on common molecular pathway(s) that are epigenetically deregulated in the pathogenesis of ALL and CLL. The correlation between methylation profile of these genes and prognosis, survival in lymphoid leukemia needs to be further evaluated in a larger number of patients.
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Zardo, Giuseppe. "The Role of H3K4 Trimethylation in CpG Islands Hypermethylation in Cancer." Biomolecules 11, no. 2 (January 22, 2021): 143. http://dx.doi.org/10.3390/biom11020143.
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CpG methylation in transposons, exons, introns and intergenic regions is important for long-term silencing, silencing of parasitic sequences and alternative promoters, regulating imprinted gene expression and determining X chromosome inactivation. Promoter CpG islands, although rich in CpG dinucleotides, are unmethylated and remain so during all phases of mammalian embryogenesis and development, except in specific cases. The biological mechanisms that contribute to the maintenance of the unmethylated state of CpG islands remain elusive, but the modification of established DNA methylation patterns is a common feature in all types of tumors and is considered as an event that intrinsically, or in association with genetic lesions, feeds carcinogenesis. In this review, we focus on the latest results describing the role that the levels of H3K4 trimethylation may have in determining the aberrant hypermethylation of CpG islands in tumors.
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Thomson, John P., Peter J. Skene, Jim Selfridge, Thomas Clouaire, Jacky Guy, Shaun Webb, Alastair R. W. Kerr, et al. "CpG islands influence chromatin structure via the CpG-binding protein Cfp1." Nature 464, no. 7291 (April 2010): 1082–86. http://dx.doi.org/10.1038/nature08924.
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Vertino, P. M., R. W. Yen, J. Gao, and S. B. Baylin. "De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase." Molecular and Cellular Biology 16, no. 8 (August 1996): 4555–65. http://dx.doi.org/10.1128/mcb.16.8.4555.
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Recent studies showing a correlation between the levels of DNA (cytosine-5-)-methyltransferase (DNA MTase) enzyme activity and tumorigenicity have implicated this enzyme in the carcinogenic process. Moreover, hypermethylation of CpG island-containing promoters is associated with the inactivation of genes important to tumor initiation and progression. One proposed role for DNA MTase in tumorigenesis is therefore a direct role in the de novo methylation of these otherwise unmethylated CpG islands. In this study, we sought to determine whether increased levels of DNA MTase could directly affect CpG island methylation. A full-length cDNA for human DNA MTase driven by the cytomegalovirus promoter was constitutively expressed in human fibroblasts. Individual clones derived from cells transfected with DNA MTase (HMT) expressed 1- to 50-fold the level of DNA MTase protein and enzyme activity of the parental cell line or clones transfected with the control vector alone (Neo). To determine the effects of DNA MTase overexpression on CpG island methylation, we examined 12 endogenous CpG island loci in the HMT clones. HMT clones expressing > or = 9-fold the parental levels of DNA MTase activity were significantly hypermethylated relative to at least 11 Neo clones at five CpG island loci. In the HMT clones, methylation reached nearly 100% at susceptible CpG island loci with time in culture. In contrast, there was little change in the methylation status in the Neo clones over the same time frame. Taken together, the data indicate that overexpression of DNA MTase can drive the de novo methylation of susceptible CpG island loci, thus providing support for the idea that DNA MTase can contribute to tumor progression through CpG island methylation-mediated gene inactivation.
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Šenigl, Filip, Jiří Plachý, and Jiří Hejnar. "The Core Element of a CpG Island Protects Avian Sarcoma and Leukosis Virus-Derived Vectors from Transcriptional Silencing." Journal of Virology 82, no. 16 (June 11, 2008): 7818–27. http://dx.doi.org/10.1128/jvi.00419-08.
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ABSTRACT Unmethylated CpG islands are known to keep adjacent promoters transcriptionally active. In the CpG island adjacent to the adenosine phosphoribosyltransferase gene, the protection against transcriptional silencing can be attributed to the short CpG-rich core element containing Sp1 binding sites. We report here the insertion of this CpG island core element, IE, into the long terminal repeat of a retroviral vector derived from Rous sarcoma virus, which normally suffers from progressive transcriptional silencing in mammalian cells. IE insertion into a specific position between enhancer and promoter sequences led to efficient protection of the integrated vector from silencing and gradual CpG methylation in rodent and human cells. Individual cell clones with IE-modified reporter vectors display high levels of reporter expression for a sustained period and without substantial variegation in the cell culture. The presence of Sp1 binding sites is important for the protective effect of IE, but at least some part of the entire antisilencing capacity is maintained in IE with mutated Sp1 sites. We suggest that this strategy of antisilencing protection by the CpG island core element may prove generally useful in retroviral vectors.
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Thompson, Reid F., Maria E. Figueroa, Ari M. Melnick, and John M. Greally. "Epigenetic Dysregulation of Candidate Cis-Regulatory Sequences in Hematological Malignancies." Blood 108, no. 11 (November 1, 2006): 2229. http://dx.doi.org/10.1182/blood.v108.11.2229.2229.
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Abstract Epigenetic changes (in particular, altered cytosine methylation) have been described in a variety of tumors. The CpG Island Methylator Phenotype (CIMP) is a well-known instance of this phenomenon wherein cytosine methylation is markedly dysregulated (normally hypomethylated loci shift to a methylated state). CIMP has been demonstrated in a number of different cancer types including hematological malignancies like AML. While methylation status has been studied predominantly at CpG islands, we used a novel assay (HELP; Khulan et al., Genome Res. 2006) to look for changes in cytosine methylation in large contiguous regions of the genome. We assessed global patterns of cytosine methylation by HELP analysis in a variety of tumor samples including leukemias and lymphomas. We found significant changes in the global methylation patterns of malignant cells, confirming prior observations of epigenetic dysregulation in these tumor types. We also discovered that the majority of the changes in cytosine methylation are occurring not at CpG islands but at other loci in the genome, including constitutively hypomethylated loci that we are finding to be candidate cis-regulatory sequences. We conclude that cytosine methylation changes in cancer occur much more extensively than analysis of CpG islands alone would indicate, and that the epigenetic dysregulation in cancer may be predominantly targeted to cis-regulatory sequences rather than to promoters.
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Sormani, Giulia, Jan O. Haerter, Cecilia Lövkvist, and Kim Sneppen. "Stabilization of epigenetic states of CpG islands by local cooperation." Molecular BioSystems 12, no. 7 (2016): 2142–46. http://dx.doi.org/10.1039/c6mb00044d.
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DNA methylation at CpG sites is an epigenetic mark that correlates with gene expresssion. Dense regions of CpG sites, so-called CpG islands, are often either fully methylated or fully unmethylated, hinting at a bistable dynamical process by which sites undergo coordinated methylation activity. We here explore a process by which CpG sites can protect others from becoming methylated, thereby re-enforcing the bistable dynamics.
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Michaelson-Cohen, Rachel, Ilana Keshet, Ravid Straussman, Merav Hecht, Howard Cedar, and Uziel Beller. "Genome-Wide De Novo Methylation in Epithelial Ovarian Cancer." International Journal of Gynecologic Cancer 21, no. 2 (January 2011): 269–79. http://dx.doi.org/10.1097/igc.0b013e31820e5cda.
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Background:DNA methylation regulates gene expression during development. The methylation pattern is established at the time of implantation. CpG islands are genome regions usually protected from methylation; however, selected islands are methylated later. Many undergo methylation in cancer, causing epigenetic gene silencing. Aberrant methylation occurs early in tumorigenesis, in a specific pattern, inhibiting differentiation.Although methylation of specific genes in ovarian tumors has been demonstrated in numerous studies, they represent only a fraction of all methylated genes in tumorigenesis.Objectives:To explore the hypermethylation design in ovarian cancer compared with the methylation profile of normal ovaries, on a genome-wide scale, thus shedding light on the role of gene silencing in ovarian carcinogenesis.Identifying genes that undergo de novo methylation in ovarian cancer may assist in creating biomarkers for disease diagnosis, prognosis, and treatment responsiveness.Methods:DNA was collected from human epithelial ovarian cancers and normal ovaries. Methylation was detected by immunoprecipitation using 5-methyl-cytosine-antibodies. DNA was hybridized to a CpG island microarray containing 237,220 gene promoter probes. Results were analyzed by hybridization intensity, validated by bisulfite analysis.Results:A total of 367 CpG islands were specifically methylated in cancer cells. There was enrichment of methylated genes in functional categories related to cell differentiation and proliferation inhibition. It seems that their silencing enables tumor proliferation.Conclusions:This study provides new perspectives on methylation in ovarian carcinoma, genome-wide. It illustrates how methylation of CpG islands causes silencing of genes that have a role in cell differentiation and functioning. It creates potential biomarkers for diagnosis, prognosis, and treatment responsiveness.
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Ogushi, Kenichiro, Atsushi Hattori, Erina Suzuki, Hirohito Shima, Masako Izawa, Hideaki Yagasaki, Reiko Horikawa, et al. "DNA Methylation Status of SHOX-Flanking CpG Islands in Healthy Individuals and Short Stature Patients with Pseudoautosomal Copy Number Variations." Cytogenetic and Genome Research 158, no. 2 (2019): 56–62. http://dx.doi.org/10.1159/000500468.
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SHOX resides in the short arm pseudoautosomal region (PAR1) of the sex chromosomes and escapes X inactivation. SHOX haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). A substantial percentage of cases with SHOX haploinsufficiency arise from pseudoautosomal copy number variations (CNVs) involving putative enhancer regions of SHOX. Our previous study using peripheral blood samples showed that some CpG dinucleotides adjacent to SHOX exon 1 were hypomethylated in a healthy woman and methylated in a woman with gross X chromosomal rearrangements. However, it remains unknown whether submicroscopic pseudoautosomal CNVs cause aberrant DNA methylation of SHOX-flanking CpG islands. In this study, we examined the DNA methylation status of SHOX-flanking CpG islands in 50 healthy individuals and 10 ISS/LWD patients with pseudoautosomal CNVs. In silico analysis detected 3 CpG islands within the 20-kb region from the translation start site of SHOX. Pyrosequencing and bisulfite sequencing of genomic DNA samples revealed that these CpG islands were barely methylated in peripheral blood cells and cultured chondrocytes of healthy individuals, as well as in peripheral blood cells of ISS/LWD patients with pseudoautosomal CNVs. These results, in conjunction with our previous findings, indicate that the DNA methylation status of SHOX-flanking CpG islands can be affected by gross X-chromosomal abnormalities, but not by submicroscopic CNVs in PAR1. Such CNVs likely disturb SHOX expression through DNA methylation-independent mechanisms, which need to be determined in future studies.
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Hu, Wei-Xin, Qiang Qu, Jiang Li, and Wei Ren. "Hyper-Methylation DAZAP2 May Suppress Its Expression in Specific Subtypes of Myeloma." Blood 114, no. 22 (November 20, 2009): 4421. http://dx.doi.org/10.1182/blood.v114.22.4421.4421.
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Abstract Abstract 4421 Most malignant features of cancer cells are triggered by activated oncogenes and the loss of tumor suppressors due to mutation or epigenetic inactivation. We previously reported that DAZAP2 was down-regulated in newly diagnosed myeloma (MM) and this may influence MM cell growth and survival. This study was undertaken to evaluate the mechanism of down-regulation DAZAP2 and determine the methylation status and loci of its promoter by using bisulphite genomic-sequencing (BGS) method in KM3 myeloma cell line. Two islands with rich GC box in the promoter of DAZAP2 gene were identified and amplified by using bisulfite-sequencing PCR (BSP). Island 1 spans -472 to -247 including 9 CpG sites (CpGs) and island 2 covers -226 to -13 including 23 CpG sites. The ratio of methylated CpGs in two CpG islands was 46.25%. The above sequences were demethylated and inserted into a pGL2-basic vector. COS-7 cells were transfected with recombinant plasmids and the activity of luciferase was evaluated. The results showed that the CpG island 1 had a weakly transcriptional activity, whereas the CpG island 2 had a strong transcriptional activity (2.38 folds compared with the positive control). The other sequence which covered CpG island 1 and 2 showed a remarkable activity (15.1 folds compared with the positive control). These data indicated that CpG island 2 of DAZAP2 gene may be hypermethylated and suppressed its expression in MM cells. We further correlated DAZAP2 expression with normal plasma cells and malignant myeloma cells, as well as the molecular subtypes which the dataset includes 8 genetic subtypes (MY, PR, LB, MS, HP, CD-1, CD-2, and MF) from 351 newly diagnosed myeloma cases (Zhan, 2006). Interestingly, we extended and confirmed our previous discovery that DAZAP2 was significantly down-regulated in MM cells by using a large uniform dataset (P = 0.004). The low expression of DAZAP2 was especially significant in the subgroups of MY, PR, LB, HP, and CD-1. This study warrants further investigation of DAZAP2 and its potential role in myeloma. Disclosures: No relevant conflicts of interest to declare.
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Angeloni, Allegra, and Ozren Bogdanovic. "Sequence determinants, function, and evolution of CpG islands." Biochemical Society Transactions 49, no. 3 (June 22, 2021): 1109–19. http://dx.doi.org/10.1042/bst20200695.
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In vertebrates, cytosine-guanine (CpG) dinucleotides are predominantly methylated, with ∼80% of all CpG sites containing 5-methylcytosine (5mC), a repressive mark associated with long-term gene silencing. The exceptions to such a globally hypermethylated state are CpG-rich DNA sequences called CpG islands (CGIs), which are mostly hypomethylated relative to the bulk genome. CGIs overlap promoters from the earliest vertebrates to humans, indicating a concerted evolutionary drive compatible with CGI retention. CGIs are characterised by DNA sequence features that include DNA hypomethylation, elevated CpG and GC content and the presence of transcription factor binding sites. These sequence characteristics are congruous with the recruitment of transcription factors and chromatin modifying enzymes, and transcriptional activation in general. CGIs colocalize with sites of transcriptional initiation in hypermethylated vertebrate genomes, however, a growing body of evidence indicates that CGIs might exert their gene regulatory function in other genomic contexts. In this review, we discuss the diverse regulatory features of CGIs, their functional readout, and the evolutionary implications associated with CGI retention in vertebrates and possibly in invertebrates.
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Rietze, Allison H., Yvette P. Conley, Dianxu Ren, Cindy M. Anderson, James M. Roberts, Arun Jeyabalan, Carl A. Hubel, and Mandy J. Schmella. "DNA Methylation of Endoglin Pathway Genes in Pregnant Women With and Without Preeclampsia." Epigenetics Insights 13 (January 2020): 251686572095968. http://dx.doi.org/10.1177/2516865720959682.
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Objective: We compared blood-based DNA methylation levels of endoglin ( ENG) and transforming growth factor beta receptor 2 ( TGFβR2) gene promoter regions between women with clinically-overt preeclampsia and women with uncomplicated, normotensive pregnancies. Methods: We used EpiTect Methyl II PCR Assays to evaluate DNA methylation of CpG islands located in promoter regions of ENG (CpG Island 114642) and TGFβR2 (CpG Island 110111). Preeclampsia was diagnosed based on blood pressure, protein, and uric acid criteria. N = 21 nulliparous preeclampsia case participants were 1:1 frequency matched to N = 21 nulliparous normotensive control participants on gestational age at sample collection (±2 weeks), smoking status, and labor status at sample collection. Methylation values were compared between case and control participant groups [( ENG subset: n = 20 (9 cases, 11 controls); TGFβR2 subset: n = 28 (15 cases, 13 controls)]. Results: The majority of the preeclampsia cases delivered at ⩾34 weeks’ gestation (83%). Average methylation levels for ENG ([M ± (SD)]; Case Participant Group = 6.54% ± 4.57 versus Control Participant group = 4.81% ± 5.08; P = .102) and TGFβR2 (Case Participant Group = 1.50% ± 1.37 vs Control Participant Group = 1.70% ± 1.40; P = .695) promoter CpG islands did not differ significantly between the participant groups. Removal of 2 extreme outliers in the ENG analytic subset revealed a trend between levels of ENG methylation and pregnancy outcome (Case Participant Group = 5.17% ± 2.16 vs Control Participant Group = 3.36% ± 1.73; P = .062). Conclusion: Additional epigenetic studies that include larger sample sizes, investigate preeclampsia subtypes, and capture methylation status of CpG island shores and shelves are needed to further inform us of the potential role that ENG and TGFβR2 DNA methylation plays in preeclampsia pathophysiology.
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Mohamad Zainal, Nurul Hayati, Nor Azlin Mohamed Ismail, and Norfilza M. Mokhtar. "Low Methylation of Matrix Metalloproteinase 1 (MMP1) is Associated with Preterm Labour in Malaysian Mothers." Sains Malaysiana 51, no. 7 (July 31, 2022): 2033–46. http://dx.doi.org/10.17576/jsm-2022-5107-08.
Full textAbstract:
Preterm births comprise 10.6% of livebirths worldwide and account for 35% of deaths among newborn babies. Understanding DNA methylation may offer basic knowledge in the understanding of pathogenesis of preterm labour. The study was undertaken to determine DNA methylation of matrix metalloproteinase 1 (MMP1) promoter in term and preterm labour using methylation-specific polymerase chain reaction (MSP). Thirty maternal venous blood samples (n=15 each) of term and preterm labour was subjected to bisulfite treatment prior to MSP. This result was then validated using DNA sequencing. Evaluation of the sequencing results by CpG islands analysis was performed using the ClustalW and SPSS software. Primers for MMP1 were located between -1226 and -1378 upstream from the transcription start site (TSS) that consisted five CpG islands. Preterm labour group had significantly lower methylated CpG islands with 39 out of total 75 (52%) compared to the term labour that has 49 out of 75 methylated CpG islands (65.33%) (t=0.694, p<0.05). Methylation occurred in 4 out of 5 methylated CpG islands in the MMP1 promoter where it only involved 2 preterm samples (13.33%) and 7 term samples (46.47%). This data suggested there were significant lower percentage of methylated MMP1 in preterm labour. Higher percentage of methylated MMP1 as observed in the term labour, will probably reduce the expression of MMP1, thus maintaining fibrillar collagen strength on the amniotic membrane and subsequently maintain the pregnancy till term. In conclusion, preterm labour has higher percentage of methylated CpG compared with term labour in MMP1 gene.
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Carlone, Diana L., and David G. Skalnik. "CpG Binding Protein Is Crucial for Early Embryonic Development." Molecular and Cellular Biology 21, no. 22 (November 15, 2001): 7601–6. http://dx.doi.org/10.1128/mcb.21.22.7601-7606.2001.
Full textAbstract:
ABSTRACT Epigenetic modification of DNA via CpG methylation is essential for the proper regulation of gene expression during embryonic development. Methylation of CpG motifs results in gene repression, while CpG island-containing genes are maintained in an unmethylated state and are transcriptionally active. The molecular mechanisms involved in maintaining the hypomethylation of CpG islands remain unclear. The transcriptional activator CpG binding protein (CGBP) exhibits a unique binding specificity for DNA elements that contain unmethylated CpG motifs, which makes it a potential candidate for the regulation of CpG island-containing genes. In order to assess the global function of this protein, mice lacking CGBP were generated via homologous recombination. No viable mutant mice were identified, indicating that CGBP is required for murine development. Mutant embryos were also absent between 6.5 and 12.5 days postcoitum (dpc). Approximately, one-fourth of all implantation sites at 6.5 dpc appeared empty with no intact embryos present. However, histological examination of 6.5-dpc implantation sites revealed the presence of embryo remnants, indicating that CGBP mutant embryos die very early in development. In vitro blastocyst outgrowth assays revealed that CGBP-null blastocysts are viable and capable of hatching and forming both an inner cell mass and a trophectoderm. Therefore, CGBP plays a crucial role in embryo viability and peri-implantation development.
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Santoro, R., M. D'Erme, S. Mastrantonio, A. Reale, S. Marenzi, H. P. Saluz, R. Strom, and P. Caiafa. "Binding of histone H1e-c variants to CpG-rich DNA correlates with the inhibitory effect on enzymic DNA methylation." Biochemical Journal 305, no. 3 (February 1, 1995): 739–44. http://dx.doi.org/10.1042/bj3050739.
Full textAbstract:
Within the H1 histone family, only some fractions enriched in the H1e-c variants are effective in causing a marked inhibition, in vitro, of enzymic DNA methylation and, in gel retardation and Southwestern blot experiments, in binding double-stranded (ds) CpG-rich oligonucleotides. Both the 6-CpG ds-oligonucleotide and the DNA purified from chromatin fractions enriched in ‘CpG islands’ are good competitors for the binding of H1e-c to 6-meCpG ds-oligonucleotide. Because of their ability to bind any DNA sequence and to suppress the enzymic methylation in any sequence containing CpG dinucleotides, these particular H1 variants could play some role in maintaining linker DNA at low methylation levels and even in preserving the unmethylated state of the CpG-rich islands which characterize the promoter regions of housekeeping genes.