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PubMed2002

Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers.

A distinctive feature of BRCA1-linked breast cancers is that they typically do not express estrogen receptor-alpha (ER(alpha)). Previous investigation suggests that methylation of CpGs within the ER(alpha) promoter mediates repression of gene expression in some ER(alpha)-negative breast cancers. To determine if methylation of CpGs within the ER(alpha) promoter is associated with BRCA1-linked breast cancers, we evaluated methylation in exon 1 of the ER(alpha) gene in 40 ER(alpha)-negative breast cancers, 20 of which were non BRCA1-linked and 20 BRCA1-linked. CpG methylation was evaluated by either methylation-sensitive restriction digest (HpaII), methylation-sensitive PCR (MSP), or direct sequencing of bisulfite-treated genomic DNA. Results from HpaII digests and MSP documented a high degree of methylation, the MSP data showing slightly higher methylation in the BRCA1-linked group. CpGs analysed by direct sequencing showed an overall average methylation of 25% among non BRCA1-linked cancers and 40% among BRCA1-linked cancers (P=0.0031). The most notable difference was found at five particular CpGs, each of which exhibited a greater than twofold increase in methylation in the BRCA1-linked group compared to the non BRCA1-linked group (P<0.03 for each CpG). Methylation of certain critical CpGs may represent an important factor in transcriptional repression of the ER(alpha) gene in BRCA1-linked breast cancers.

Adult↗
PubMed1997

Prader-Willi and Angelman syndromes: diagnosis with a bisulfite-treated methylation-specific PCR method.

The putative promoter region of the SNRPN gene contains a CpG island which is heavily methylated in the maternally derived allele and unmethylated in the paternally derived allele. In patients with Prader-Willi syndrome (PWS) only the methylated allele is present, while in those with Angelman syndrome (AS) only the unmethylated allele is present. The purpose of this paper is to report a polymerase chain reaction (PCR)-based assay to evaluate methylation status of the CpG island of the SNRPN gene and to show that this assay allows rapid diagnosis of PWS and AS. Methylated cytosines in the CpG dinucleotide are resistant to chemical modification by sodium bisulfite. In contrast, bisulfite treatment converts all unmethylated cytosines to uracil. Based on this differential effect, the bisulfite-modified DNA sequence of a methylated allele was successfully distinguished from that of an unmethylated allele using 2 sets of allele-specific primer pairs: a methylated allele-specific primer pair (MET) and an unmethylated allele-specific primer pair (UNMET). Bisulfite-modified DNA from 10 patients with PWS amplified only with the MET pair while modified DNA from 5 patients with AS amplified only with the UNMET pair. Modified DNA from 50 normal unrelated individuals amplified with both primer pairs. In that methylation-specific PCR (MSPCR) can detect all presently testable causes of PWS and AS in a rapid and cost-effective fashion, serious consideration should be given to the use of this test in the initial evaluation of all patients in which PWS or AS is being considered.

Angelman Syndrome↗
PubMed2004

Frequent silencing of fragile histidine triad gene (FHIT) in Burkitt's lymphoma is associated with aberrant hypermethylation.

The fragile histidine triad (FHIT) gene, a potential tumor-suppressor gene, is frequently inactivated in multiple human cancers. However, the FHIT gene remains largely unexplored in Burkitt's lymphoma (BL). Hence, we assessed whether loss of FHIT expression occurs in BL, and, if so, what is the mechanism of such loss. Lack of protein expression was observed in 50% of BL cell lines. Methylation-specific polymerase chain reaction (MSP) showed that 45% of BL cell lines carried aberrantly methylated FHIT alleles. Sequencing of bisulfite-treated DNA confirmed these data and indicated a very high density of methylation in all methylated alleles. Real-time, quantitative reverse-transcription PCR analysis indicated that attenuation of full-length FHIT transcription was correlated with methylation. Sequencing of transcripts illustrated that aberrant transcription resulting in loss of FHIT exons occurred more commonly in BL containing unmethylated FHIT genes. However, such transcripts often coexisted with full-length FHIT transcripts. Not surprisingly, therefore, loss of FHIT protein in BL correlated with CpG island methylation, rather than with aberrant transcription. FHIT methylation also was detected in 31% (16 of 51) of the primary BLs examined, including 2 samples whose derived cell lines also manifested FHIT hypermethylation. Aberrant methylation can thus occur in vivo. In summary, this report provides evidence that epigenetic modification frequently results in loss of FHIT expression in BL.

Acid Anhydride Hydrolases↗
PubMed1998

Demethylation by 5-aza-2'-deoxycytidine of specific 5-methylcytosine sites in the promoter region of the retinoic acid receptor beta gene in human colon carcinoma cells.

The role of retinoic acid receptor beta(RARbeta), a putative tumor suppressor gene, in the development of colon malignancy still remains to be clarified. We reported previously that the expression of RARbeta in DLD-1 human colon adenocarcinoma cells was silenced by DNA methylation at the level of the promoter region (Anti-Cancer Drugs 1997; 8: 56). In addition, we observed that RARbeta expression could be activated by the hypomethylating action of 5-aza-2'-deoxycytidine (5-Aza-CdR). In this report we have identified, by sequencing of bisulfite-modified DNA of DLD-1 colon tumor cells, the specific 5-methylcytosine positions in the region of -46 to +251 bp from the transcription start site of RARbeta2. We observed that 5-Aza-CdR treatment demethylated these specific sites. Based on this sequence data, specific primers for the methylation-specific PCR (MSP) assay were designed to discriminate methylated from unmethylated CpG sites in the promoter region of RARbeta. This assay confirmed the changes in the methylation status of the RARbeta gene in DLD-1 colon tumor cells before and after treatment with 5-Aza-CdR. The methylation status of the promoter region of the RARbeta gene was also examined in primary human colon adenocarcinomas using the MSP assay. Six of the 14 colon tumor samples showed signs of hypermethylation of this gene. The MSP assay for RARbeta may be a useful tool to clarify the role of DNA methylation for this gene in colon tumorigenesis.

5-Methylcytosine↗
PubMed2006

SPAN-Xb expression in myeloma cells is dependent on promoter hypomethylation and can be upregulated pharmacologically.

SPAN-Xb is a novel cancer-testis antigen in multiple myeloma (MM). In this study, we determined the mechanisms regulating SPAN-Xb expression in MM. SPAN-Xb promoter sequence was first cloned into the CAT-reporter vector to determine the role of promoter methylation in the regulation of gene expression. Tumor cells were treated with 5-azacytidine and a panel of cytokines were used to determine their ability to induce SPAN-Xb expression. Bisulfite conversion with sequence analysis was applied to a panel of tumor cells and normal tissues to correlate the CpG dinucleotide hypomethylation and SPAN-Xb expression. We found that SPAN-Xb promoter function could be silenced by methylation. 5-Azacytidine induced promoter hypomethylation and resulted in SPAN-Xb expression, at both the transcript and protein levels. Hypomethylation of the CpG dinucleotides at positions -310, -307, -299 and -221 within the SPAN-Xb promoter strongly predict for SPAN-Xb expression. Both IL-7 and GM-CSF were also able to upregulate the expression of SPAN-Xb in myeloma cells, but only after the promoter sequence has been hypomethylated. Our results provide the first evidence showing the role of promoter methylation in the primary regulation of SPAN-Xb and the ability of IL-7 and GM-CSF to further enhance SPAN-Xb gene and protein expression in myeloma cells.

Azacitidine↗
PubMed2004

Double-stranded siRNA targeted to the huntingtin gene does not induce DNA methylation.

RNA interference is an evolutionarily conserved mechanism of post-transcriptional gene silencing. Small interfering RNAs (siRNA) of 21-23 nucleotides generated from processing double-stranded RNA (dsRNA) by ribonuclease III, Dicer, are widely used for selective sequence-specific gene silencing in a broad range of organisms. In plants, siRNA is associated with de novo RNA-directed DNA methylation (RdDM) at the homologous target genomic region. To examine RdDM in somatic cells, human glioblastoma cell lines were treated with siRNAs homologous to the human huntingtin gene responsible for Huntington's disease. Methylation of CpG dinucleotides in the plasmid vectors expressing the dsRNAs and homologous genomic region was investigated by bisulfite-mediated genomic sequencing. Target regions of the siRNA in the huntingtin gene showed no significant change in the pattern of DNA methylation, and no CpG methylation was observed on the plasmid vectors. These results indicate that siRNA is not directly linked to DNA methylation at the target huntingtin genomic locus in human cells.

Cell Line, Tumor↗
PubMed2002

A rapid, quantitative, non-radioactive bisulfite-SNuPE- IP RP HPLC assay for methylation analysis at specific CpG sites.

The precise mapping and quantification of DNA methylation as an epigenetic parameter during development and in diseased tissues is of great importance for functional genomics. Here we describe a rapid, quantitative method to assess methylation levels at specific CpG sites using PCR products of bisulfite-treated genomic DNA. Using single nucleotide primer extension (SNuPE) assays in combination with ion pair reverse phase high performance liquid chromatography (IP RP HPLC) separation techniques, methylated and unmethylated CpGs can be discriminated and quantified based on the different masses and hydrophobicities of the extended primer products. The assay is linear, highly reproducible and several sites can be measured simultaneously in one reaction. It can be semi-automated and eliminates the need for cloning and sequencing of individual bisulfite PCR products.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Analysis of methylation patterns in the regulatory region of the latent Epstein-Barr virus promoter BCR2 by automated fluorescent genomic sequencing.

We analyzed the methylation patterns of CpG dinucleotides in the regulatory region of the latent Epstein-Barrvirus (EBV) promoter BCR2 (also called C promoter, Cp) using automated fluorescent genomic sequencing after bisulfite-induced modification of DNA. BCR2 is one of the alternative promoters for transcripts encoding the growth-transformation-associated nuclear antigens EBNA 1-6 which are expressed in a host cell phenotype dependent manner. Well characterized clones isolated from the Burkitt's lymphoma (BL) line Mutu differing from each other as to their phenotype and EBV latent gene expression were used in the present study. We found that in Mutu BL III clone 99 which is actively using the BCR2 promoter the regulatory sequences are unmethylated with two exceptions (position 10702 and 10799). In contrast, there are 15 methylated cytosines in the same region in Mutu BL I clone 216 where the BCR2 promoter is silent. Cytosines which are potential targets of DNA methyltransferase in the immediate vicinity or within the attachment sites of cellular C promoter binding factors CBF1 and CBF2 remained hypomethylated in Mutu BL I clone 216. This suggests a role for a hypermethylated region (nucleotides 10666 -10865, -639 to -440 bases upstream from the beginning of the TATA box at position 11305) in silencing of the BCR2 promoter in these cells.

Base Sequence↗
PubMed2002

An analytical method for the detection of methylation differences at specific chromosomal loci using primer extension and ion pair reverse phase HPLC.

We have developed a rapid, accurate, and quantitative method for the detection of methylation differences at specific CpG sites based on bisulfite treatment of DNA followed by primer extension and ion-pair reversed-phase high performance liquid chromatography (IP RP HPLC). The application of the method is illustrated by analysis of differentially imprinted alleles arising from Prader-Willi and Angelman syndromes. In order to convert unmethylated cytosines to uracil, plasmid and genomic DNA samples were treated with sodium bisulfite and the targeted sequence was then amplified using oligodeoxynucleotide primers specific for the bisulfite-deaminated DNA. The PCR product(s) from this step was used as a template for a primer extension reaction and the products were subsequently analyzed chromatographically using IP RP HPLC. This method eliminates the need to use restriction enzymes to determine the methylation status of the amplicon and circumvents the need for radio labeling for the quantitative measurements. Finally, this method removes the need for nucleotide sequencing because it is not solely reliant on the presence or absence of one or more PCR products, as is the case with related methods.

Ampicillin Resistance↗
PubMed2001

Epigenetics of latent Epstein-Barr virus genomes: high resolution methylation analysis of the bidirectional promoter region of latent membrane protein 1 and 2B genes.

We analysed the methylation patterns of CpG dinucleotides in a bidirectional promoter region (LRS, LMP 1 regulatory sequences) of latent Epstein-Barr virus (EBV) genomes using automated fluorescent genomic sequencing after bisulfite-induced modification of DNA. Transcripts for two latent membrane proteins, LMP 1 (a transforming protein) and LMP 2B, are initiated in this region in opposite directions. We found that B cell lines and a clone expressing LMP 1 carried EBV genomes with unmethylated or hypomethylated LRS, while highly methylated CpG dinucleotides were present at each position or at discrete sites and within hypermethylated regions in LMP 1 negative cells. Comparison of high resolution methylation maps suggests that CpG methylation-mediated direct interference with binding of nuclear factors LBF 2, 3, 7, AML1/LBF1, LBF5 and LBF6 or methylation of CpGs within an E-box sequence (where activators as well as repressors can bind) is not the major mechanism in silencing of the LMP 1 promoter. Although a role for CpG methylation within binding sites of Sp1 and 3, ATF/CRE and a sis-inducible factor (SIF) cannot be excluded, hypermethylation of LRS or regions within LRS in LMP 1 negative cells suggests a role for an indirect mechanism, via methylcytosine binding proteins, in silencing of the LMP 1 promoter.

CpG Islands↗
PubMed2000

Inactivation of p16INK4a in primary tumors and cell lines of head and neck squamous cell carcinoma.

Inactivation of the p16INK4a gene by mutation and deletion is common in head and neck squamous cell carcinoma (HNSCC). The present study demonstrates that hypermethylation of the 5' CpG islands can serve as an alternative mechanism for the inactivation of the p16INK4a gene in this tumor. We studied 11 HNSCC cell lines and 17 oral squamous cell carcinoma (OSCC) primary tumors for p16INK4a gene status by protein/mRNA and DNA genetic/epigenetic analyses to determine the incidence of its inactivation. Our study indicates that: (1) inactivation of p16 protein is frequent in HNSCC cell lines (6/11, 54.5%) and OSCC primary tumors (15/17, 88.2%), (2) inactivation of p16INK4a protein is commonly associated with the presence of gene alteration such as mutation, homozygous deletion and especially aberrant methylation, and (3) genomic sequencing of bisulfite-modified DNA shows that the carcinoma develops a heterogeneous pattern of hypermethylation.

Aged↗
PubMed1997

DNA methylation patterns in the calcitonin gene region at first diagnosis and at relapse of acute lymphoblastic leukemia (ALL).

Aberrant DNA methylation can occur early in neoplastic transformation and may lead to the development of cancer. We describe the alterations of methylation patterns at the DNA sequence level which occurred in the 5' region of the calcitonin gene in lymphoblasts from 14 pediatric patients with acute lymphoblastic leukemia (ALL). The DNA methylation status of 25 CpG sites was determined by sequence analysis after bisulfite treatment of the DNA. This method showed that 13 out of 14 patients had increased numbers of methylated CpG sites in the calcitonin gene region at initial diagnosis when compared to control DNA from healthy individuals. The 5' region of the calcitonin gene appears to be methylated to a significantly higher degree in T lineage ALL compared to B lineage ALL (P < 0.01). Each of six ALL patients who were investigated at initial diagnosis and at relapse showed alterations in DNA methylation between the two stages. These six cases were also investigated by Southern blot analysis with methylcytosine-sensitive restriction enzymes and this method showed an increase in DNA methylation in only four of the six cases. The DNA sequencing method thus appears to be better suited to assess alterations of DNA methylation than Southern blot analysis. There are marked regional differences in the frequency of methylation of individual CpG sites and in the frequency of alterations between the two stages. Our results show that alterations in DNA methylation continue to occur from the initial stage to the relapse stage of ALL, suggesting that aberrant DNA methylation may play a role in tumor progression.

Base Sequence↗
PubMed2002

Hypermethylation of the human telomerase catalytic subunit (hTERT) gene correlates with telomerase activity.

DNA methylation is an epigenetic process involved in embryonic development, differentiation and aging. It is 1 of the mechanisms resulting in gene silencing in carcinogenesis, especially in tumor suppressor genes (e.g., p16, Rb). Telomerase, the DNA polymerase adding TTAGGG repeats to the chromosome end, is involved in the regulation of the replicative life span by maintaining telomere length. This enzyme is activated in germ and stem cells, repressed in normal somatic cells and reactivated in a large majority of tumor cells. The promoter region of the hTERT gene, encoding for the catalytic subunit of human telomerase, has been located in a CpG island and may therefore be regulated at least in part by DNA methylation. We analyzed the methylation status of 27 CpG sites within the hTERT promoter core region by methylation-sensitive single-strand conformation analysis (MS-SSCA) and direct sequencing using bisulfite-modified DNA in 56 human tumor cell lines, as well as tumor and normal tissues from different organs. A positive correlation was observed among hypermethylation of the hTERT promoter, hTERT mRNA expression and telomerase activity (p < 0.00001). Furthermore, this correlation was confirmed in normal tissues where hypermethylation of the hTERT promoter was found exclusively in hTERT-expressing telomerase-positive samples and was absent in telomerase-negative samples (p < 0.00002). Since tumor tissues contain also nonneoplastic stromal elements, we performed microdissection to allow confirmation that the hTERT promoter methylation truly occurred in tumor cells. Our results suggest that methylation may be involved in the regulation of hTERT gene expression. To our knowledge, this is the first gene in which methylation of its promoter sequence has been found to be positively correlated with gene expression.

DNA Methylation↗
PubMed2005

Decreased expression and frequent allelic inactivation of the RUNX3 gene at 1p36 in human hepatocellular carcinoma.

BACKGROUND/AIMS: Alteration in transforming growth factor-beta signaling pathway is one of the main causes of hepatocellular carcinoma (HCC). The human runt-related transcription factor 3 gene (RUNX3) is an important component of this pathway. RUNX3 locus 1p36 is commonly deleted in a variety of human cancers, including HCC. Therefore, we examined genetic and epigenetic alterations of RUNX3 in human HCC. METHODS: Five HCC cell lines and 41 patients with HCC were investigated in this study. We examined the expression of RUNX3 mRNA, methylation status of RUNX3 promoter region, loss of heterozygosity (LOH) at 1p36, and mutation analysis. These results were compared with clinicopathological data. RESULTS: Promoter hypermethylation was detected in four (80%) of five HCC cell lines and 31 (75.6%) of 41 HCC tissues, confirmed by sequence of bisulfite-treated DNA. LOH was detected in 14 (37.8%) of 37 HCC. By comparison with clinicopathological data, hypermethylation was more common in hepatitis C virus antibody and formation of capsule-positive cases, and decrease of expression was correlated strongly with advanced stage and LOH-detected cases. CONCLUSION: Hypermethylation and LOH appear to be common mechanisms for inactivation of RUNX3 in HCC. Therefore, RUNX3 may be an important tumor suppressor gene related to hepatocarcinogenesis.

Alleles↗
PubMed1998

Analysis of DNA methylation of the 5' region of the deoxycytidine kinase gene in CCRF-CEM-sensitive and cladribine (CdA)- and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA)-resistant cells.

DNA methylation of the CpG-rich 5' region of the deoxycytidine kinase (dCK) gene is potentially involved in the suppression of the gene and the resistance of tumour cells to arabinosylcytosine (ara-C). 2-Chlorodeoxyadenosine (cladribine, CdA) and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA) are purine nucleoside analogues which are also phosphorylated by dCK. We observed a reduction in dCK activity in a number of CCRF-CEM-derived cell lines that are resistant to these drugs and hypothesized that this reduction is due to DNA methylation of the 5' region of the dCK gene. The DNA methylation state was analyzed at the DNA sequence level after bisulfite modification of genomic DNA. The investigated region included 0.3 kb of DNA upstream to the start site of transcription, exon 1 and part of intron 1. Sensitive cells (CCRF-CEM/0) and three resistant cell lines (CCRF-CEM/CdA4000, CCRF-CEM/CAFdA100 and CCRF-CEM/CAFdA4000) were investigated. The region that was analyzed contained no methylated cytosine residues in the parental cell line CCRF-CEM/0 or in the resistant cell lines. Therefore, it is highly unlikely that DNA methylation plays a role in the suppression of dCK gene expression in these cell lines.

Adenine Nucleotides↗
PubMed2003

Glucose metabolism in cancer. Evidence that demethylation events play a role in activating type II hexokinase gene expression.

One of the "signature" phenotypes of highly malignant, poorly differentiated tumors, including hepatomas, is their remarkable propensity to utilize glucose at a much higher rate than normal cells, a property frequently dependent on the marked overexpression of type II hexokinase (HKII). As the expression of the gene for this enzyme is nearly silent in liver tissue, we tested the possibility that DNA methylation/demethylation events may be involved in its regulation. Initial studies employing methylation restriction endonuclease analysis provided evidence for differential methylation patterns for the HKII gene in normal hepatocytes and hepatoma cells, the latter represented by a highly glycolytic model cell line (AS-30D). Subsequently, sequencing following sodium bisulfite treatment revealed 18 methylated CpG sites within a CpG island (-350 to +781 bp) in the hepatocyte gene but none in that of the hepatoma. In addition, treatment of a hepatocyte cell line with the DNA methyltransferase inhibitors, 5'-azacytidine and 5'-aza-2'-deoxycytidine, activated basal expression levels of HKII mRNA and protein. Finally, stably transfecting the hepatocyte cell line with DNA demethylase also resulted in activating the basal expression levels of HKII mRNA and protein. These novel observations indicate that one of the initial events in activating the HKII gene during either transformation or tumor progression may reside at the epigenetic level.

Animals↗
PubMed1997

Epigenetic variation illustrated by DNA methylation patterns of the fragile-X gene FMR1.

Genomic methylation patterns of mammals can vary among individuals and are subject to dynamic changes during development. In order to gain a better understanding of this variation, we have analyzed patterns of cytosine methylation within a 200 bp region at the CpG island of the human FMR1 gene from leukocyte DNA. FMR1 is normally methylated during inactivation of the X chromosome in females and it is also methylated and inactivated upon expansion of CGG repeats in fragile-X syndrome. Patterns of methylation (epigenotypes) were determined by the sequencing of bisulfite-treated alleles from normal males and females and alleles from a family of five brothers who are methylation mosaics and are affected to various degrees by the fragile-X syndrome. Our data indicate that: (i) methylation of individual CpG cytosines is strikingly variable in hypermethylated epigenotypes obtained from a single individual, suggesting that maintenance of cytosine methylation is a dynamic process; (ii) methylation of non-CpG cytosines in the region studied may occur but is rare; (iii) mosaicism of methylation in the analyzed fragile-X males is remarkably similar to that found for the active X and inactive X alleles in normal females, suggesting that the methylation mosaicism of some fragile-X males reflects similar on and off states of FMR1 expression that exist in normal females; (iv) hypermethylation is slightly more pronounced on fragile-X alleles than on normal inactive X alleles of females; (v) the general dichotomy of hypo- and hypermethylated alleles persisted over the 5 year period that separated samplings of the fragile-X males; (vi) methylation variability was most pronounced at a consensus binding sequence for the alpha-PAL transcription factor, a sequence that may play a role in regulating expression of FMR1.

Alleles↗
PubMed2005

Demethylation of the MCJ gene in stage III/IV epithelial ovarian cancer and response to chemotherapy.

OBJECTIVE: Methylation of a CpG island within the Methylation controlled DNAJ (MCJ) gene results in loss of expression in normal and neoplastic cells. Normal ovarian surface epithelial cells are methylated at the MCJ CpG island and do not express the MCJ gene. Furthermore, re-expression of the MCJ gene, in ovarian cancer cell lines, has been correlated with increased sensitivity to several important chemotherapeutic drugs. The objective of this study was to determine the extent of MCJ promoter methylation in epithelial ovarian cancer patients and address the possible role of MCJ methylation levels in response to chemotherapy in ovarian cancer patients. METHODS: The methylation status of 35 CpG sites within the MCJ CpG island was determined by sequencing of sodium bisulfite modified tumor DNA in 41 patients with stage III/IV epithelial ovarian tumors. Levels of methylation of the MCJ CpG island were then compared with response to therapy and overall survival in the patients. RESULTS: The analysis identified frequent loss of MCJ methylation in ovarian tumors, with only a subset retaining high methylation levels. While 93% (38/41) of tumors examined showed some level of MCJ methylation, only 17% (7/41) retained very high levels (>90% methylation). The presence of such high levels of CpG island methylation correlated significantly with poor response of patients' tumors to therapy (P = 0.027) and poor overall survival (P = 0.023, hazard ratio = 2.9). CONCLUSIONS: These results suggest that MCJ methylation may be useful as a marker of response to chemotherapy in ovarian cancer and are consistent with previous in vitro data linking loss of MCJ expression with drug resistance.

Base Sequence↗