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CpG Dinucleotides (cpg + dinucleotide)
Selected AbstractsDNA methylation: an epigenetic pathway to cancer and a promising target for anticancer therapyJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 8 2002Jesper Worm Abstract The unique properties of a cancer cell are acquired through a stepwise accumulation of heritable changes in the information content of proto-oncogenes and tumor suppressor genes. While gain, loss, and mutation of genetic information have long been known to contribute to tumorigenesis, it has been increasingly recognized over the past 5 years that ,epigenetic' mechanisms may play an equally important role. The main epigenetic modification of the human genome is methylation of cytosine residues within the context of the CpG dinucleotide. De novo methylation of ,CpG islands' in the promoter regions of tumor suppressor genes may lead to transcriptional silencing through a complex process involving histone deacetylation and chromatin condensation, and thus represents a tumorigenic event that is functionally equivalent to genetic changes like mutation and deletion. DNA methylation is interesting from a diagnostic viewpoint because it may be easily detected in DNA released from neoplastic and preneoplastic lesions into serum, urine or sputum, and from a therapeutic viewpoint because epigenetically silenced genes may be reactivated by inhibitors of DNA methylation and/or histone deacetylase. A better understanding of epigenetic mechanisms leading to tumor formation and chemoresistance may eventually improve current cancer treatment regimens and be instructive for a more rational use of anticancer agents. [source] Cellular activation by plasmid DNA in various macrophages in primary cultureJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2008Hiroyuki Yoshida Abstract Macrophages are an important group of cells responsible for the inflammatory response to unmethylated CpG dinucleotide (CpG motif) in plasmid DNA (pDNA) via Toll-like receptor 9 (TLR9). This finding is primarily based on in vitro studies. Previous in vivo studies also have suggested that tissue macrophages are involved in inflammatory cytokine release in the circulation following intravenous administration of pDNA to mice. However, the relationship between the in vitro and in vivo studies has not been sufficiently clarified. To gain insight into which types of cells are responsible for the production of cytokines upon interaction with pDNA, peritoneal macrophages, splenic macrophages, hepatic nonparenchymal cells (NPCs) including Kupffer cells and mesangial cells were isolated from mice. All types of primary cultured cells, except for mesangial cells, express TLR9 at varying levels. Splenic macrophages and hepatic NPCs were activated to produce tumor necrosis factor-, (TNF-,) by naked pDNA, whereas peritoneal macrophages and mesangial cells were not. pDNA complexed with N -[1-(2,3-dioleyloxy)propyl]- N,N,N -trimethyl-ammonium chloride/cholesterol liposome induced TNF-, in the splenic macrophages but not in the other cell types. These results indicate that splenic macrophages and hepatic NPCs are closely involved in TNF-, production in response to pDNA. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4575,4585, 2008 [source] CpG methylation of the CENP-B box reduces human CENP-B bindingFEBS JOURNAL, Issue 1 2005Yoshinori Tanaka In eukaryotes, CpG methylation is an epigenetic DNA modification that is important for heterochromatin formation. Centromere protein B (CENP-B) specifically binds to the centromeric 17 base-pair CENP-B box DNA, which contains two CpG dinucleotides. In this study, we tested complex formation by the DNA-binding domain of CENP-B with methylated and unmethylated CENP-B box DNAs, and found that CENP-B preferentially binds to the unmethylated CENP-B box DNA. Competition analyses revealed that the affinity of CENP-B for the CENP-B box DNA is reduced nearly to the level of nonspecific DNA binding by CpG methylation. [source] Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3bGENES TO CELLS, Issue 7 2006Akiko Tsumura DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b cooperatively regulate cytosine methylation in CpG dinucleotides in mammalian genomes, providing an epigenetic basis for gene silencing and maintenance of genome integrity. Proper CpG methylation is required for the normal growth of various somatic cell types, indicating its essential role in the basic cellular function of mammalian cells. Previous studies using Dnmt1,/, or Dnmt3a,/,Dnmt3b,/, ES cells, however, have shown that undifferentiated embryonic stem (ES) cells can tolerate hypomethylation for their proliferation. In an attempt to investigate the effects of the complete loss of CpG DNA methyltransferase function, we established mouse ES cells lacking all three of these enzymes by gene targeting. Despite the absence of CpG methylation, as demonstrated by genome-wide methylation analysis, these triple knockout (TKO) ES cells grew robustly and maintained their undifferentiated characteristics. TKO ES cells retained pericentromeric heterochromatin domains marked with methylation at Lys9 of histone H3 and heterochromatin protein-1, and maintained their normal chromosome numbers. Our results indicate that ES cells can maintain stem cell properties and chromosomal stability in the absence of CpG methylation and CpG DNA methyltransferases. [source] Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: Summary of mutations (including 23 novel) and modeling of TGase-1,HUMAN MUTATION, Issue 4 2009Matthew L. Herman Abstract Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare cornification diseases. Germline mutations in TGM1 are the most common cause of ARCI in the United States. TGM1 encodes for the TGase-1 enzyme that functions in the formation of the cornified cell envelope. Structurally defective or attenuated cornified cell envelop have been shown in epidermal scales and appendages of ARCI patients with TGM1 mutations. We review the clinical manifestations as well as the molecular genetics of ARCI. In addition, we characterized 115 TGM1 mutations reported in 234 patients from diverse racial and ethnic backgrounds (Caucasion Americans, Norwegians, Swedish, Finnish, German, Swiss, French, Italian, Dutch, Portuguese, Hispanics, Iranian, Tunisian, Moroccan, Egyptian, Afghani, Hungarian, African Americans, Korean, Japanese and South African). We report 23 novel mutations: 71 (62%) missense; 20 (17%) nonsense; 9 (8%) deletion; 8 (7%) splice-site, and 7 (6%) insertion. The c.877-2A>G was the most commonly reported TGM1 mutation accounting for 34% (147 of 435) of all TGM1 mutant alleles reported to date. It had been shown that this mutation is common among North American and Norwegian patients due to a founder effect. Thirty-one percent (36 of 115) of all mutations and 41% (29 of 71) of missense mutations occurred in arginine residues in TGase-1. Forty-nine percent (35 of 71) of missense mutations were within CpG dinucleotides, and 74% (26/35) of these mutations were C>T or G>A transitions. We constructed a model of human TGase-1 and showed that all mutated arginines that reside in the two beta-barrel domains and two (R142 and R143) in the beta-sandwich are located at domain interfaces. In conclusion, this study expands the TGM1 mutation spectrum and summarizes the current knowledge of TGM1 mutations. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of 5, methylated CpG dinucleotides. Hum Mutat 0, 1,12, 2009. © 2009 Wiley-Liss, Inc. [source] The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene,HUMAN MUTATION, Issue 4 2006Michael E. Baser Abstract Constitutional heterozygous inactivating mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene cause the autosomal dominant disease NF2, and biallelic inactivating somatic NF2 mutations are found in a high proportion of unilateral sporadic vestibular schwannoma (USVS) and sporadic meningioma. We surveyed the distributions of constitutional NF2 mutations in 823 NF2 families, 278 somatic NF2 mutations in USVS, and 208 somatic NF2 mutations in sporadic meningioma. Based on the available NF2 mutation data, the most dominant influence on the spectra of mutations in exons 1,15 are C>T transitions that change arginine codons (CGA) to stop codons (TGA) due to spontaneous deamination of methylcytosine to thymine in CpG dinucleotides. The paucity of reported mutations in exon 9 and the absence of reported mutations in exons 16 and 17 may be related to structure,function relationships in the NF2 protein. Hum Mutat 27(4), 297-306, 2006. © 2006 Wiley-Liss, Inc. [source] DNA methylation and histone modification regulate silencing of OPG during tumor progression,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2009Tung-Ying Lu Abstract The identification of molecules that are down-regulated in malignant phenotype is important for understanding tumor biology and their role in tumor suppression. We compared the expression profile of four normal nasal mucosal (NNM) epithelia and a series of nasopharyngeal cancinoma (NPC) cell lines using cDNA microarray and confirmed the actual expression of the selected genes, and found osteoprotegerin (OPG) to be ubiquitously deficient in NPC cells. We also found OPG to be down-regulated in various cancer cell lines, including oral, cervical, ovarian, lung, breast, pancreas, colon, renal, prostate cancer, and hepatoma. Administration of recombinant OPG (rOPG) brought about a reduction in cancer cell growth through apoptotic mechanism. We generated eleven monoclonal antibodies (MAbs) against OPG to study OPG's expression and biological functions in cancer cells. OPG was detected in the tumor stromal regions, but not in the cancer cell per se in surgical specimens of liver cancer. Quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR) revealed that OPG was down-regulated in NPC tissues compared with normal nasal polyp (NNP) tissues. In addition, we showed OPG silencing to be associated with promoter methylation as well as histone modifications. In OPG-silenced cancer cell lines, the OPG gene promoter CpG dinucleotides were highly methylated. Compared to normal cells, silenced OPG gene in cancer cells were found to have reduced histone 3 lysine 4 tri-methylation (H3K4me3) and increased histone 3 lysine 27 tri-methylation (H3K27me3). Taken together, these results suggest that OPG silencing in carcinoma cancer cells occurs through epigenetic repression. J. Cell. Biochem. 108: 315,325, 2009. © 2009 Wiley-Liss, Inc. [source] Promoter methylation in circadian genes of endometrial cancers detected by methylation-specific PCRMOLECULAR CARCINOGENESIS, Issue 10 2006Mu-Chin Shih Abstract Methylation of CpG dinucleotides in the promoter sequence of a gene can lead to deregulated and suppressed gene expression. In this study, we have developed procedures for methylation-specific polymerase chain reaction (MSP) and sequencing analysis to determine CpG methylation status of the promoter sequences of nine circadian genes in 35 endometrial cancers (EC) and paired noncancerous endometrial tissues. DNA methylation was found in the promoter sequences of PER1, PER2, and CRY1, but not of other six circadian genes in the ECs and normal tissues examined. Eleven of the 35 EC tissues showed CpG methylation in the promoter sequences of PER1, PER2, or CRY1. Of these 11 cases, 1 had promoter methylation in all the three genes, 1 in PER1 and PER2, 3 in PER1 and CRY1, and 6 in PER1, respectively. In comparison, promoter CpG methylation of PER1, PER2, or CRY1 was found in only 7 of 35 paired noncancerous tissues including 2 in PER1 and PER2, 2 in PER1, and 3 in CRY1. In summary, promoter methylation in the PER1, PER2, or CRY1 circadian genes was detected in about one-third of EC and one-fifth of noncancerous endometrial tissues of 35 paired specimens indicating possible disruption of the circadian clock in the development of EC. © 2006 Wiley-Liss, Inc. [source] Oral immunization with Porphyromonas gingivalis outer membrane protein and CpG oligodeoxynucleotides elicits T helper 1 and 2 cytokines for enhanced protective immunityMOLECULAR ORAL MICROBIOLOGY, Issue 3 2010C. Liu Summary The aim of this study was to evaluate the efficacy of an oral vaccine containing the 40-kDa outer membrane protein of Porphyromonas gingivalis (40K-OMP) and synthetic oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG ODN) to control oral infection by P. gingivalis. Oral immunization with 40K-OMP plus CpG ODN induced significant 40K-OMP-specific serum immunoglobulin G (IgG), IgA, and saliva IgA antibody responses. The 40K-OMP-specific CD4+ T cells induced by oral 40K-OMP plus CpG ODN produced both T helper type 1 (Th1; interferon-,) and Th2 (interleukin-4) cytokines. Furthermore, increased frequencies of CD11c+ B220+ dendritic cells (DCs) and CD11c+ CD11b+ DCs with upregulated expression of CD80, CD86, CD40, and major histocompatibility complex class II molecules were noted in spleen, Peyer's patches, and cervical lymph nodes. Immunized mice were then infected orally with P. gingivalis to determine whether the immune responses induced by oral 40K-OMP plus CpG ODN were capable of suppressing the bone resorption caused by P. gingivalis infection. Mice given 40K-OMP plus CpG ODN showed significantly reduced bone loss associated with oral infection by P. gingivalis. Oral administration of 40K-OMP together with CpG ODN induces Th1-type and Th2-type cells, which provide help for protective immunity against P. gingivalis infection. This may be an important tool for the prevention of chronic periodontitis. [source] Epigenetic changes in cancer,APMIS, Issue 10 2007KIRSTEN GRØNBÆK A cancer develops when a cell acquires specific growth advantages through the stepwise accumulation of heritable changes in gene function. Basically, this process is directed by changes in two different classes of genes: Tumor suppressor genes that inhibit cell growth and survival and oncogenes that promote cell growth and survival. Since several alterations are usually required for a cancer to fully develop, the malignant phenotype is determined by the compound status of tumor suppressor genes and oncogenes. Cancer genes may be changed by several mechanisms, which potentially alter the protein encoding nucleotide template, change the copy number of genes, or lead to increased gene transcription. Epigenetic alterations, which, by definition, comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence, are increasingly being recognized for their roles in carcinogenesis. These epigenetic alterations may involve covalent modifications of amino acid residues in the histones around which the DNA is wrapped, and changes in the methylation status of cytosine bases (C) in the context of CpG dinucleotides within the DNA itself. Methylation of clusters of CpGs called "CpG-islands" in the promoters of genes has been associated with heritable gene silencing. The present review will focus on how disruption of the epigenome can contribute to cancer. In contrast to genetic alterations, gene silencing by epigenetic modifications is potentially reversible. Treatment by agents that inhibit cytosine methylation and histone deacetylation can initiate chromatin decondensation, demethylation and reestablishment of gene transcription. Accordingly, in the clinical setting, DNA methylation and histone modifications are very attractive targets for the development and implementation of new therapeutic approaches. Many clinical trials are ongoing, and epigenetic therapy has recently been approved by the United States Food and Drug Administration (US FDA) for use in the treatment of myelodysplastic syndrome (MDS) and primary cutaneous T-cell lymphoma (CTCL). [source] Anti-HBV effects of CpG oligodeoxynucleotide-activated peripheral blood mononuclear cells from patients with chronic hepatitis B,APMIS, Issue 10 2005NING LI Unmethylated CpG dinucleotides in bacterial DNA or synthetic oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG ODN) are known as a potent Th1-like immune enhancer in vertebrates. Chronic hepatitis B is the immunocompromising condition. We therefore investigated the effects of CpG ODN on cultured cells from chronic hepatitis B patients and healthy controls. The inhibitory effects of CpG ODN on hepatitis B virus (HBV) were also studied. The secretion of IFN-, by CpG ODN-activated peripheral blood mononuclear cells (PBMCs) from chronic hepatitis B patients and healthy controls was significantly increased when compared with PBMCs alone or GpC ODN-stimulated PBMCs. After activation with CpG ODN, the IFN-, secretion by chronically HBV-infected patient PBMCs is less than that by healthy control PBMCs. Treatment of HepG2 2.2.15 cells with culture supernatants of PBMCs activated by CpG ODN can significantly suppress the secretion of HBsAg, HBeAg and HBV DNA as compared with that of PBMCs without CpG ODN activation under the same conditions. No inhibitory effect on the replication of HBV was found for CpG ODN treatment alone. Our results indicated that CpG ODN could efficiently enhance the immune response of chronic hepatitis B patients. Moreover, the CpG ODN-activated PBMCs from chronic hepatitis B patients were able to significantly inhibit HBV replication in vitro, suggesting that CpG ODN may be a potential immunoregulator against HBV infection in the future. [source] | ||||||||||||||||