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PubMed2003

The role of DNA methylation in setting up chromatin structure during development.

DNA methylation inhibits gene expression in animal cells, probably by affecting chromatin structure. Biochemical studies suggest that this process may be mediated by methyl-specific binding proteins that recruit enzymatic machinery capable of locally altering histone modification. To test whether DNA methylation actually has a role in the assembly of chromatin during normal development, we used cell transfection and a transgene construct genetically programmed to be either methylated or unmethylated in all cell types of the mouse. Chromatin immunoprecipitation (ChIP) analysis shows that the presence of DNA methylation brings about the deacetylation of histone H4 and methylation of Lys9 of histone H3 (H3 Lys9) and prevents methylation of Lys4 of histone H3 (H3 Lys4), thus generating a structure identical to that of methylated sequences in the genome. These results indicate that the methylation pattern established in early embryogenesis is profoundly important in setting up the structural profile of the genome.

Acetylation↗
PubMed1995

Identification of a 68 kDa protein species as a specific DNA-binding component of the H3abp complex interacting with the histone H3.2 G1/S regulatory domain.

The hamster histone H3.2 promoter contains a protein binding site (referred to as site X) required for G1/S transcriptional activation. We report here that nuclear extracts prepared from serum synchronized cells at various stages of the cell cycle show a biphasic increase in the H3.2 specific complex, H3abp, binding to site X. An increase in binding activity occurs as cells first enter the cell cycle and later at the G1/S border. The H3.2 specific binding activity is enhanced by Mg2+ and Ca2+ in vitro, but is inhibited by Zn2+. Site X resembles a Jun/AP-1 site, but previously it has been shown that the H3abp complex is immunologically distinct from the characterized AP-1 proteins. Here, we identify the size of the hamster nuclear protein(s) that bind specifically to the H3abp site by ultra-violet crosslinking and renaturation of specific protein bands following gel electrophoresis. In addition, we purify H3abp by affinity chromatography and show that the purified H3abp has a different methylation interference profile from AP-1. Our results indicate that a protein species around 68 kDa is the major DNA binding component of the H3abp complex and it binds specifically to the histone promoter site required for G1/S regulation.

Animals↗
PubMed2006

Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics.

PURPOSE: To delineate clinically relevant molecular signatures of intracranial ependymoma. MATERIALS AND METHODS: We analyzed 24 primary intracranial ependymomas. For genomic profiling, microarray-based comparative genomic hybridization (CGH) was used and results were validated by fluorescent in situ hybridization and loss of heterozygosity mapping. We performed gene expression profiling using microarrays, real-time quantitative reverse transcriptase polymerase chain reaction, and methylation analysis of selected genes. We applied class comparison analyses to compare both genomic and expression profiling data with clinical characteristics. RESULTS: A variable number of genomic imbalances were detected by array CGH, revealing multiple regions of recurrent gain (including 2q23, 7p21, 12p, 13q21.1, and 20p12) and loss (including 5q31, 6q26, 7q36, 15q21.1, 16q24, 17p13.3, 19p13.2, and 22q13.3). An ependymoma-specific gene expression signature was characterized by the concurrent abnormal expression of developmental and differentiation pathways, including NOTCH and sonic hedgehog signaling. We identified specific differentially imbalanced genomic clones and gene expression signatures significantly associated with tumor location, patient age at disease onset, and retrospective risk for relapse. Integrated genomic and expression profiling allowed us to identify genes of which the expression is deregulated in intracranial ependymoma, such as overexpression of the putative proto-oncogene YAP1 (located at 11q22) and downregulation of the SULT4A1 gene (at 22q13.3). CONCLUSION: The present exploratory molecular profiling study allowed us to refine previously reported intervals of genomic imbalance, to identify novel restricted regions of gain and loss, and to identify molecular signatures correlating with various clinical variables. Validation of these results on independent data sets represents the next step before translation into the clinical setting.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Epigenetic inactivation of MCJ (DNAJD1) in malignant paediatric brain tumours.

MCJ (DNAJD1) is a recently discovered member of the DNAJ protein family whose expression is controlled epigenetically by methylation of a CpG island located within the 5' transcribed region of its gene. Methylation-dependent transcriptional silencing of MCJ has been observed in ovarian cancers and associated with increased resistance to chemotherapeutic agents; however, its role in other cancer types has not been widely investigated. We examined the status of MCJ in intracranial primitive neuroectodermal tumours [PNETs, comprising cerebellar PNETs (medulloblastomas) and supratentorial PNETs (stPNETs)] and ependymomas, together representing the most common malignant brain tumours of childhood. Evidence of MCJ hypermethylation was found in all 3 tumour types [medulloblastomas, 3/9 (33%) cell lines, 2/28 (7%) primary tumours; stPNETs, 2/2 (100%) cell lines, 3/10 (30%) primary tumours; and ependymomas, 2/20 (10%) primary tumours] but not in nonneoplastic brain tissues (n = 11), indicating that MCJ methylation is a tumour-specific event. In methylated cases, the distribution of methylated CpG sites across the CpG island could be broadly divided into 2 patterns: (i) extensive methylation of the majority of CpG sites across the island or (ii) limited methylation of individual CpG sites concentrated towards the 5' end of the island. Extensive methylation patterns were associated with the methylation-dependent transcriptional silencing of MCJ in medulloblastoma and stPNET cell lines. Further investigations of the mechanism of MCJ inactivation revealed that its loss could occur either through biallelic epigenetic methylation or by methylation in association with genetic loss of its second allele. These data indicate that epigenetic inactivation of MCJ may play a role in the development of a range of paediatric brain tumour types, and its role in disease pathogenesis and chemotherapeutic resistance should now be investigated further.

Adolescent↗
PubMed2006

Epigenetic alterations in intraductal papillary mucinous neoplasms of the pancreas.

Intraductal papillary mucinous neoplasm (IPMN), an increasingly recognized cystic neoplasm of the pancreas with a broad spectrum of malignant potential, has been considered a precursor to infiltrating ductal adenocarcinoma. Because of its unique clinical, radiological, pathological, and molecular features, IPMN has attracted considerable interest among clinicians and researchers. Although some genetic alterations have been described in IPMNs, the molecular features that characterize the evolution and progression of these neoplasms are largely unknown. Recent studies have shown that aberrant methylation of the promoter cytosine-phospho-guanine (CpG) island is a common mechanism associated with the silencing of tumor-suppressor and cancer-related genes in IPMNs. Importantly, the prevalence of such methylation increases along with the grade of neoplasia, suggesting that these epigenetic events may contribute to the progression of IPMNs. Further studies of epigenetic alterations in IPMN will shed light on the molecular pathogenesis of this unique neoplasm and lead to the identification of epigenetic markers that can be applied in the clinical setting.

Adenocarcinoma, Mucinous↗
PubMed2004

Organization, differential expression and methylation of rDNA in artificial Solanum allopolyploids.

Uniparental activity of ribosomal RNA genes (rDNA) in interspecific hybrids is known as nucleolar dominance (ND). To see if difference in rDNA intergenic spacers (IGS) might be correlated with ND, we have used artificial Solanum allopolyploids and back-crossed lines. Combining fluorescence in situ hybridization and quantification of the level of the rRNA precursor by real-time PCR, we demonstrated that an expression hierarchy exists: In leaves, roots, and petals of the respective allopolyploids, rDNA of S lycopersicum (tomato) dominates over rDNA of S. tuberosum (potato), whereas rDNA of S. tuberosum dominates over that of the wild species S. bulbocastanum . Also in a monosomic addition line carrying only one NOR-bearing chromosome of tomato in a potato background the dominance effect was maintained. These results demonstrate that there is possible correlation between transcriptional dominance and number of conservative elements downstream of the transcription start in the Solanum rDNA. In anthers and callus tissues under-dominant rDNA was slightly (S. lycopersicum/S. tuberosum) or strongly (S. tuberosum/S. bulbocastanum) expressed indicating developmental modulation of ND. In leaves and petals, repression of the respective parental rDNA correlated with cytosine methylation at certain sites conserved in the IGS, whereas activation of under-dominant rDNA in anthers and callus tissues was not accompanied by considerable changes of the methylation pattern.

Base Sequence↗
PubMed2004

Molecular cloning and characterization of LCRG1 a novel gene localized to the tumor suppressor locus D17S800-D17S930.

Laryngeal carcinoma (LC) is the most commonly diagnosed malignancy and recently the incidence of this disease has increased. By means of the mRNA differential display method we identified a cDNA, Laryngeal carcinoma related gene 1 (LCRG1) which has significantly reduced expression in 40% (12/30) of primary LCs and in 6 of 10 various cancer cell lines. Northern Blot analysis showed that LCRG1 was expressed more abundantly in human heart, pancreas, skeletal muscle, and in murine testis, liver, brain and heart than in other tissues. The cDNA sequence of this gene is identical to part of the sequence of PAC HCIT75G16 clone (GenBank accession No. AC003042) from the chromosome band 17q12-21.1 which is one of the most common loss of heterozygosity (LOH) regions involved in LC, prostate cancer, etc. This gene is composed of six exons and spans about 60 kb of genomic DNA with a 3.4 kb mature transcript. The alignment of this gene with STS markers localized the gene to the previously identified tumor-suppressor locus D17S800-D17S930. The putative protein encoded by this gene is 288 amino acid with one potential site for phosphorylation by casein kinase II and no significant homology to any known proteins in the public databases. The primary tumor suppressive functions (proliferation rate,soft agar growth and tumor formation) were observed in a LC cell line (Hep-2) by lipofectin transfection. Together these data strongly suggest a potential role of LCRG1 contributing to the development of LC.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Methylation and expression analysis of 15 genes and three normally-methylated genes in 13 Ovarian cancer cell lines.

Aberrant methylation of CpG islands (CGIs) in promoter regions of tumor-suppressor genes causes their silencing, and aberrant demethylation of normally methylated CGIs in promoter regions causes aberrant expression of cancer-testis antigens. Here, we comprehensively analyzed aberrant methylation of 15 genes and demethylation of three normally methylated genes in 13 ovarian cancer cell lines. RASSF1A was most frequently methylated (complete methylation in 7 and partial methylation in 4 cell lines), followed by ESR1 (5 and 2, respectively), FLNC (4 and 4), HAND1 (4 and 2), LOX (3 and 2), HRASLS (3 and 2), MGMT (3 and 0), CDKN2A (3 and 0), THBD (2 and 1), hMLH1 (2 and 0), CDH1 (1 and 1) and GSTP1 (1 and 0). hTERC and TIMP3 were only partially methylated in 7 and 2 cell lines, respectively. BRCA1 was not methylated at all. Aberrant demethylation of MAGE-A3, -B2 and -A1 was detected in 8, 4 and 3 cell lines, respectively. Gene expression was consistently absent in cell lines without unmethylated DNA molecules. Aberrant methylation was frequently observed in MCAS, RMUG-L (mucinous cell carcinomas), RTSG (poorly-differentiated carcinoma) and TYK-nu (undifferentiated carcinoma) while infrequent in HTOA, JHOS-2, and OV-90 (serous cell carcinomas). Aberrant demethylation was frequently observed in OV-90, OVK-18, and ES-2 cell lines. It was shown that aberrant methylation and demethylation were frequently observed in ovarian cancer cell lines, and these data will provide a basis for further epigenetic analysis in ovarian cancers.

DNA Methylation↗
PubMed2006

Larger numbers of silenced genes in cancer cell lines with increased de novo methylation of scattered CpG sites.

Methylation of scattered CpG sites within a CpG island (CGI), denoted as "methylation seeds", is proposed to serve as a precursor of dense methylation of the CGI. We examined whether or not an abnormal increase of methylation seeds is associated with a larger number of methylation-silenced genes. Two gastric cancer cell lines with increased seeds (AGS and KATO-III) and two cell lines without (HSC39 and HSC57) were treated with equivalent doses of a demethylating agent, 5-aza-2'-deoxycytidine. Oligonucleotide microarray analysis showed that 25, 63, 9 and 1 genes with promoter CGIs, respectively, were up-regulated at 16-fold or more. By methylation analysis, it was estimated that 24, 41, 4 and 1 gene, respectively, were silenced due to methylation of promoter CGIs. Notably, AGS and KATO-III had silencing of genes expressed in the normal stomach while HSC39 and HSC57 had few. The association between the increase of methylation seeds and larger numbers of silenced genes suggested that the increase can induce gene silencing overriding their transcription.

Azacitidine↗
PubMed2006

Methods for detecting DNA methylation in tumors: from bench to bedside.

Tumor-acquired changes in DNA methylation are the focus of research in an increasing number of basic, translational, and clinical laboratories around the world. In the laboratory, genome-wide technologies such as expression and DNA microarrays have been adapted to analyze patterns of DNA methylation and to screen for novel disease markers. Other technologies that are relatively inexpensive and highly sensitive such as methylation-specific PCR (MSP), or quantitative, such as quantitative MSP and pyrosequencing are widely used in retrospective studies and have potential in a diagnostic setting. In the near future, it may be possible to screen patients for common cancers using DNA methylation signatures as well as to measure patient responses to treatment, to identify patients at increased risk, or to monitor interventions designed to reduce cancer incidence. In this article, we review genome-wide and quantitative, high- resolution methods for methylation analysis that are used in the laboratory and clinic, and discuss their potential for use in a clinical setting.

Chromosome Mapping↗
PubMed2006

Localized methylation in the key regulator gene endothelin-1 is associated with cell type-specific transcriptional silencing.

DNA methylation can contribute to the stable transcriptional silencing of mammalian genes. Often times, these genes are important developmental regulators, and their silencing in cell types where they are not supposed to be active is important for the phenotypic stability of the cells. To identify key developmental regulator genes whose expression in terminally differentiated cells may be inhibited by DNA methylation, mouse dermal fibroblasts were demethylated with 5-aza-2'-deoxycytidine, and changes in gene expression monitored by microarray analysis. Endothelin-1 (Et1 or Edn1), which encodes a cytokine with diverse regulatory functions, was among the genes upregulated following demethylation. We found that CpG dinucleotides within a short region in intron 1 of the gene have dramatically higher levels of methylation in Et1-non-expressing fibroblasts and chondrocytes as compared to the Et1-expressing mouse cell line, mIMCD-3. Strong evolutionary conservation of this region implies its role in the cis-regulation of Et1 transcription. To confirm that should Et1 in dermal fibroblasts become aberrantly activated, it could indeed lead to the dysregulation of many downstream genes, we exposed fibroblasts to exogenous ET1 peptide and assayed for transcriptional changes by microarray. ET1 treatment resulted in significant expression changes - primarily downregulation - of a significant number of genes. In particular, Tgfbeta2 and Tgfbeta3 were among the downregulated genes, which in turn alter the expression status of their many target genes. These data suggest that the stable silencing of Et1 through its associated DNA methylation in intron 1 is critical for the developmental stability of dermal fibroblasts, and perhaps other cell types as well.

Animals↗
PubMed2005

Aberrant methylation of FBN2 in human non-small cell lung cancer.

FBN2, a large modular extracellular matrix glycoprotein, is known to be a key component of human elastic fiber. A loss of FBN2 expression due to promoter methylation was recently identified in pancreatic cancer. We examined FBN2 expression by reverse transcription PCR and aberrant methylation of FBN2 by methylation specific PCR in lung cancer cell lines. Aberrant methylation of FBN2 was present in 55% (6 of 11) of non-small cell lung cancer (NSCLC) cell lines, but it absent in small cell lung cancer cell lines. The concordance between loss of expression and aberrant methylation of FBN2 was 88% (14 of 16) in the cell lines. FBN2 expression was restored after treatment with the demethylating agent, 5-aza-2'-deoxycytidine in all six cell lines tested that lacked FBN2 expression. Among primary NSCLC, 49% (62/126) of cases had FBN2 methylation, but only 7% (5/69) of the corresponding nonmalignant lung tissues had it. Although FBN2 methylation was detected even in patients with early stage disease, it occurred frequently in large tumors (p=0.022), with nodal metastasis (p=0.037), or with advanced stages of NSCLC (p=0.014). Methylation and silencing of FBN2 in tumor cells may play an important role in carcinogenesis, invasion, and metastasis of NSCLC.

Aged↗
PubMed2005

Differentiating mechanisms of toxicity using global gene expression analysis in Saccharomyces cerevisiae.

Genotoxic stress triggers a variety of biological responses including the transcriptional activation of genes regulating DNA repair, cell survival and cell death. Genomic approaches, which monitor gene expressions across large numbers of genes, can serve as a powerful tool for exploring mechanisms of toxicity. Here, using five different agents, we investigated whether the analysis of genome-wide expression profiles in Saccharomyces cerevisiae could provide insights into mechanisms of genotoxicity versus cytotoxicity. To differentiate the genotoxic stress-associated expression signatures from that of a general cytotoxic stress, we compared gene expression profiles following the treatment with DNA-reactive (cisplatin, MMS, bleomycin) and DNA non-reactive (ethanol and sodium chloride) compounds. Although each of the tested chemicals produced a distinct gene expression profile, we were able to identify a gene expression signature consisting of a relatively small number of biologically relevant genes capable of differentiating genotoxic and cytotoxic stress. The gene set includes such upregulated genes as HUG1, ECM4 and previously uncharacterized gene, YLR297W in the genotoxic and GAP1, CGR1 in the cytotoxic group. Our results indicate the potential of gene expression profile analysis for elucidating mechanism of action of genotoxic agents.

Alkylating Agents↗
PubMed2004

Gene structure and expression of the 5'-(CGG)(n)-3'-binding protein (CGGBP1).

The human nuclear 5'-(CGG)(n)-3'-binding protein (CGGBP1) influences the expression of the fragile X mental retardation (FMR1) gene by specifically interacting with the 5'-(CGG)(n>5)-3' repeat in its 5' untranslated region. Here, we show that CGGBP1 binds to 5'-(CGG)(n)-3' repeats with n>or=5 and to interrupted repeats. The genomic and mRNA organization of the human and murine CGGBP1 genes was studied and the human gene was mapped to chromosome 3p. Due to alternative polyadenylation, mRNAs of 1.2 and 4.5 kb are transcribed at varying ratios in human and murine cells and in embryonic, fetal, and adult tissues. The human and the murine genes, including promoters and large parts of the untranslated regions, are highly conserved. A sequence of 235 nucleotides 5' upstream of CGGBP1 is essential for promoter activity in transfection experiments. Complete in vitro methylation inactivates the promoter, which is unmethylated in human cells as shown by bisulfite genomic sequencing.

Alternative Splicing↗
PubMed2005

Growth delay of human pancreatic cancer cells by methylase inhibitor 5-aza-2'-deoxycytidine treatment is associated with activation of the interferon signalling pathway.

Alteration of methylation status has been recognized as a possible epigenetic mechanism of selection during tumorigenesis in pancreatic cancer. This type of cancer is characterized by poor prognosis partly due to resistance to conventional drug treatments. We have used microarray technology to investigate the changes in global gene expression observed after treatment of different pancreatic cancer cell lines with the methylase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR). We have observed that this agent is able to inhibit to various degrees the growth of three pancreatic cancer cell lines. In particular, this inhibition was associated with induction of interferon (IFN)-related genes, as observed in other tumour types. Thus, expression of STAT1 seems to play a key role in the cellular response to treatment with the cytosine analogue. Moreover, we found increased p21(WAF1) and gadd45A expression to be associated with the efficacy of the treatment; this induction may correlate with activation of the IFN signalling pathway. Expression of the p16(INK) protein was also linked to the ability of cells to respond to 5-aza-CdR. Finally, genome-wide demethylation induced sensitization that significantly increased response to further treatment with various chemotherapy agents.

Antimetabolites, Antineoplastic↗
PubMed2001

Comparison of the antimicrobial tolerance of oxytetracycline-resistant heterotrophic bacteria isolated from hospital sewage and freshwater fishfarm water in Belgium.

The aim of this study was to investigate the relationship between antimicrobial tolerance and taxonomic diversity among the culturable oxytetracycline-resistant (Ot(r)) heterotrophic bacterial population in two Belgian aquatic sites receiving wastewater either from human medicine or from aquaculture. The study of Ot(r) heterotrophs and mesophilic Aeromonas spp. allowed comparison of tolerance data at the intergenus as well as at the intragenus level. In total, 354 independently obtained Ot(r) isolates were subjected to antimicrobial tolerance testing and identified by GLC analysis of their cellular fatty acid methyl esters (FAMEs), by API 20E profiling and/or by Fluorescent Amplified Fragment Length Polymorphism (FAFLP) DNA fingerprinting. In general, Ot(r) hospital heterotrophs displayed a higher frequency (84%) of ampicillin (Amp) tolerance compared to the Ot(r) heterotrophs from the freshwater fishfarm site (22%). FAME results indicated that this effect was linked to the predominance of intrinsically ampicillin-resistant Ot(r) Aeromonas strains over representatives of Acinetobacter and Escherichia coli within the hospital strain set. Among the Ot(r) mesophilic Aeromonas strain set, the global tolerance profiles of the two sites only differed in a higher number of kanamycin (Kan) -tolerant strains (43%) for hospital aeromonads in comparison with the fishfarm aeromonads (8%). To some extent, this finding was correlated with the specific presence of Aeromonas caviae DNA hybridisation group (HG) 4. Collectively, these results suggest that the profiles for Amp and Kan tolerance observed in both sites arose from taxonomic differences in the culturable Ot(r) bacterial population at the generic or subgeneric level. In addition, our identification data also revealed that Enterobacter sp., Stenotrophomonas maltophilia, and A. veronii biovar sobria HG8 may be considered potential indicator organisms to assess microbial tolerance in various compartments of the aquatic environment.

Aeromonas↗
PubMed2004

A computational search for box C/D snoRNA genes in the Drosophila melanogaster genome.

MOTIVATION: In eukaryotes, the family of non-coding RNA genes includes a number of genes encoding small nucleolar RNAs (mainly C/D and H/ACA snoRNAs), which act as guides in the maturation or post-transcriptional modifications of target RNA molecules. Since in Drosophila melanogaster (Dm) only few examples of snoRNAs have been identified so far by cDNA libraries screening, integration of the molecular data with in silico identification of these types of genes could throw light on their organization in the Dm genome. RESULTS: We have performed a computational screening of the Dm genome for C/D snoRNA genes, followed by experimental validation of the putative candidates. Few of the 26 confirmed snoRNAs had been recognized by cDNA library analysis. Organization of the Dm genome was also found to be more variegated than previously suspected, with snoRNA genes nested in both the introns and exons of protein-coding genes. This finding suggests that the presence of additional mechanisms of snoRNA biogenesis based on the alternative production of overlapping mRNA/snoRNA molecules. AVAILABILITY: Additional information is available at http://www.bioinformatica.unito.it/bioinformatics/snoRNAs.

Animals↗
PubMed2006

Abnormal CpG island methylation occurs during in vitro differentiation of human embryonic stem cells.

Directed differentiation of human embryonic stem cells (hESCs) into specific somatic cells holds great promise for cell replacement therapies. However, it is unclear if in vitro hESC differentiation causes any epigenetic abnormality such as hypermethylation of CpG islands. Using a differential methylation hybridization method, we identified 65 CpG islands (out of 4608 CpG islands or 1.4%) that exhibited increased DNA methylation during the conversion of hESCs into neural progenitor/stem cells (NPCs). These methylated CpG islands belong to genes in cell metabolism, signal transduction and cell differentiation, which are distinctively different from oncogenic CpG island hypermethylation observed in cancer-related genes during tumorigenesis. We further determined that methylation in these CpG islands, which is probably triggered by de novo DNA methyltransferase Dnmt3a, is abnormally higher in hESC-NPCs than in primary NPCs and astrocytes. Correlating with hypermethylation in promoter CpG islands of metabolic enzyme gene CPT1A and axoneme apparatus gene SPAG6, levels of CPT1A and SPAG6 mRNAs are significantly reduced in hESC-NPCs when compared with hESCs or primary neural cells. Because CPT1A is involved in lipid metabolism and CPT1A deficiency in human is associated with the hypoketotic hypoglycemia disorder, the reduced CPT1A expression in hESC-NPCs raises a potential concern for the suitability of these cells in cell transplantation. Collectively, our data show that abnormal CpG island methylation takes place in a subset of genes during the differentiation/expansion of hESC derivatives under current culture conditions, which may need to be monitored and corrected in future cell transplantation studies.

Astrocytes↗