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PubMed2004

Stability and strand asymmetry in the non-B DNA structure at the bcl-2 major breakpoint region.

The t(14;18) translocation involving the Ig heavy chain locus and the BCL-2 gene is the single most common chromosomal translocation in human cancer. Recently we reported in vitro and in vivo chemical probing data indicating that the 150-bp major breakpoint region (Mbr), which contains three breakage subregions (hotspots) (known as peaks I, II, and III), has single-stranded character and hence a non-B DNA conformation. Although we could document the non-B DNA structure formation at the bcl-2 Mbr, the structural studies were limited to chemical probing. Therefore, in the present study, we used multiple methods including circular dichroism to detect the non-B DNA at the bcl-2 Mbr. We established a new gel shift method to detect the altered structure at neutral pH on shorter DNA fragments containing the bcl-2 Mbr and analyzed the fine structural features. We found that the single-stranded region in the non-B DNA structure observed is stable for days and is asymmetric with respect to the Watson and Crick strands. It could be detected by oligomer probing, a bisulfite modification assay, or a P1 nuclease assay. We provide evidence that two different non-B conformations exist at peak I in addition to the single one observed at peak III. Finally we used mutagenesis and base analogue incorporation to show that the non-B DNA structure formation requires Hoogsteen pairing. These findings place major constraints on the location and nature of the non-B conformations assumed at peaks I and III of the bcl-2 Mbr.

Base Sequence↗
PubMed1999

A methylation PCR approach for detection of fragile X syndrome.

Fragile X syndrome is associated with the expansion of the number of CGG trinucleotide tandem repeats at the 5' untranslated region of the FMR1 gene. The number of CGG trinucleotide repeats in normal individuals ranges between 5 and 50, in asymptomatic carrier individuals it ranges between 50 and 200, and in affected individuals it is more than 200 CGG repeats. In addition, in affected individuals the cytosine residues in the CGG repeats and the adjacent CpG island are methylated and the FMR1 gene is transcriptionally inactive. The most common diagnostic method for the detection of the syndrome is Southern blot analysis. Methods based on the polymerase chain reaction (PCR) could facilitate the rapid screening of large numbers of individuals by accurately determining the number of CGG repeats. Current PCR techniques for amplification of CGG repeats are, however, inefficient and unreliable because of their 100% C+G composition. Thus, most of the described PCR protocols require subsequent Southern blot analysis and autoradiography. We present a novel PCR approach for the diagnosis of fragile X syndrome based on the methylation-sensitive conversion of C residues to U by bisulfite on single-strand DNA and subsequent amplification of the antisense strand with specific primers. A PCR with primers for methylated C residues will amplify the CpG dinucleotide region upstream to CGG repeats exclusively in affected males. As a result of extensive mismatch between primers and bisulfite-treated DNA, no PCR fragments will be obtained in normal and transmitting males. Moreover, the bisulfite treatment dramatically reduces the C+G component of the region; thus, the high Tm and the strong secondary structures are no longer obstacles for PCR amplification. In normal and carrier individuals, UUG repeats (previously 3'-CCG-5') in the antisense strand can easily be amplified and visualized on a gel by ethidium bromide staining. We applied our method on 25 males previously diagnosed by Southern blot analysis. All the samples were easily and accurately diagnosed. The method has considerable advantages compared with other diagnostic tests for fragile X syndrome.

Base Sequence↗
PubMed2001

Targeted random mutagenesis to identify functionally important residues in the D2 protein of photosystem II in Synechocystis sp. strain PCC 6803.

To identify important residues in the D2 protein of photosystem II (PSII) in the cyanobacterium Synechocystis sp. strain PCC 6803, we randomly mutagenized a region of psbDI (coding for a 96-residue-long C-terminal part of D2) with sodium bisulfite. Mutagenized plasmids were introduced into a Synechocystis sp. strain PCC 6803 mutant that lacks both psbD genes, and mutants with impaired PSII function were selected. Nine D2 residues were identified that are important for PSII stability and/or function, as their mutation led to impairment of photoautotrophic growth. Five of these residues are likely to be involved in the formation of the Q(A)-binding niche; these are Ala249, Ser254, Gly258, Ala260, and His268. Three others (Gly278, Ser283, and Gly288) are in transmembrane alpha-helix E, and their alteration leads to destabilization of PSII but not to major functional alterations of the remaining centers, indicating that they are unlikely to interact directly with cofactors. In the C-terminal lumenal tail of D2, only one residue (Arg294) was identified as functionally important for PSII. However, from the number of mutants generated it is likely that most or all of the 70 residues that are susceptible to bisulfite mutagenesis have been altered at least once. The fact that mutations in most of these residues have not been picked up by our screening method suggests that these mutations led to a normal photoautotrophic phenotype. A novel method of intragenic complementation in Synechocystis sp. strain PCC 6803 was developed to facilitate genetic analysis of psbDI mutants containing several amino acid changes in the targeted domain. Recombination between genome copies in the same cell appears to be much more prevalent in Synechocystis sp. strain PCC 6803 than was generally assumed.

Amino Acid Sequence↗
PubMed1998

Molecular aspects of neoplasia of Syrian hamster cells transformed in vitro by chemical carcinogens.

The addition of environmental agents (carcinogens) induces transformation that can be quantitated. Its frequency follows a linear relationship with dose and is consistent with a 'one hit' phenomenon. Transformed colonies produce transformed lines with attributes of neoplastic cells including production of tumors. The results parallel in vivo activity. Although, molecular analysis of most animal assay indicate the presence of activated oncogenes belonging to the ras family, ras activation is a low frequency event in the neoplastic conversion of Syrian hamster cells just as is found with human malignancies. In our analysis of 22 independently derived lines N-ras activation was found only with sodium bisulfite transformed lines. A novel oncogene named carcinogenesis promotion hamster (cph) because its association with the carcinogenic process has been identified. This resulted from focusing on Syrian hamster cells transformed with a single dose of 3-methylcholanthrene (MCA) and cosmid-rescue-techniques from a third-cycle NIH3T3 transformant obtained by sequential transfections of genomic DNA from MCA-initiated hamster fetal cells. cph transforms NIH3T3 cells and acts synergistically with Ha-ras to transform murine fibroblasts. Gene expression analysis using cph genomic fragments from normal and neoplastic cells identifies a number of transcripts including a major mRNA of 2.5 kb as well as several larger transcripts. cph is actively transcribed in different tissues and different species. In the hamster it is a single copy gene localized by FISH to the euchromatic short arm of the X chromosome, at region Xpa7. cph does not have any significant global homology to sequences deposited in date banks, confirming that it is a novel gene. The transforming gene codes for a truncated 246 amino acids whereas the normal cph has a residue of 469 amino acids. In conclusion cph oncogene is activated by a single point-mutation; its activation appears an important mechanism for the conversion of carcinogen treated hamster cells to malignancy and because homologous sequences occur in human DNA it may also be important to the neoplastic conversion of human cells.

3T3 Cells↗
PubMed1975

The structural basis for the resistance of Escherichia coli formylmethionyl transfer ribonucleic acid to cleavage by Escherichia coli peptidyl transfer ribonucleic acid hydrolase.

Escherichia coli formylmethionly-tRNA-tMet is unique among N-acylaminoacyl-tRNAs in its resistance to cleavage by peptidyl-tRNA hydrolase. Chemical modification of tRNA-fMet with sodium bisulfite converts fMet-tRNA-fMet into a good substrate for the hydrolase. The products of the enzymatic cleavage are free tRNA-fMet and formylmethionine. Bisulfite treatment produces cytidine to uridine base changes at several sites in the tRNA structure. One of these modifications results in formation of a new hydrogen-bonded base pair at the end of the acceptor stem of tRNA-fMet. We have shown that this modification is responsible for the observed change in biological activity. Enzymatic cleavage appears to be facilitated by the presence of a 5-terminal phosphate at the end of a fully base-paired acceptor stem, because removal of the 5-phosphate group from N-acetylphenylalanyl-tRNA-Phe or bisulfite-modified fMet-tRNA-FMet reduced the rate of hydrolysis of these substrates. The unpaired base at the 5 terminus of unmodified fMet-tRNA-fMet appears to reduce susceptibility of the tRNA to hydrolytic attack both by positioning the 5-phosphate in an unfavorable orientation and by directly interfering with enzymatic binding. The unusual structure of the acceptor stem of this E. coli tRNA thus plays a critical role in maintaining the viability of the organism by preventing enzymatic cleavage of the fMet group from the bacterial initiator tRNA.

Amino Acyl-tRNA Synthetases↗
PubMed2003

Epigenetic detection of human chromosome 14 uniparental disomy.

The recent demonstration of genomic imprinting of DLK1 and MEG3 on human chromosome 14q32 indicates that these genes might contribute to the discordant phenotypes associated with uniparental disomy (UPD) of chromosome 14. Regulation of imprinted expression of DLK1 and MEG3 involves a differentially methylated region (DMR) that encompasses the MEG3 promoter. We exploited the normal differential methylation of the DLK1/MEG3 region to develop a rapid diagnostic PCR assay based upon an individual's epigenetic profile. We used methylation-specific multiplex PCR in a retrospective analysis to amplify divergent lengths of the methylated and unmethylated MEG3 DMR in a single reaction and accurately identified normal, maternal UPD14, and paternal UPD14 in bisulfite converted DNA samples. This approach, which is based solely on differential epigenetic profiles, may be generally applicable for rapidly and economically screening for other imprinting defects associated with uniparental disomy, determining loss of heterozygosity of imprinted tumor suppressor genes, and identifying gene-specific hypermethylation events associated with neoplastic progression.

Chromosomes, Human, Pair 14↗
PubMed2001

DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes.

ICF (immunodeficiency, centromeric region instability and facial anomalies) is a recessive disease caused by mutations in the DNA methyltransferase 3B gene (DNMT3B). Patients have immunodeficiency, chromosome 1 (Chr1) and Chr16 pericentromeric anomalies in mitogen-stimulated lymphocytes, a small decrease in overall genomic 5-methylcytosine levels and much hypomethylation of Chr1 and Chr16 juxtacentromeric heterochromatin. Microarray expression analysis was done on B-cell lymphoblastoid cell lines (LCLs) from ICF patients with diverse DNMT3B mutations and on control LCLs using oligonucleotide arrays for approximately 5600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested. A set of 32 genes had consistent and significant ICF-specific changes in RNA levels. Half of these genes play a role in immune function. ICF-specific increases in immunoglobulin (Ig) heavy constant mu and delta RNA and cell surface IgM and IgD and decreases in Ig(gamma) and Ig(alpha) RNA and surface IgG and IgA indicate inhibition of the later steps of lymphocyte maturation. ICF-specific increases were seen in RNA for RGS1, a B-cell specific inhibitor of G-protein signaling implicated in negative regulation of B-cell migration, and in RNA for the pro-apoptotic protein kinase C eta gene. ICF-associated decreases were observed in RNAs encoding proteins involved in activation, migration or survival of lymphoid cells, namely, transcription factor negative regulator ID3, the enhancer-binding MEF2C, the iron regulatory transferrin receptor, integrin beta7, the stress protein heme oxygenase and the lymphocyte-specific tumor necrosis factor receptor family members 7 and 17. No differences in promoter methylation were seen between ICF and normal LCLs for three ICF upregulated genes and one downregulated gene by a quantitative methylation assay [combined bisulfite restriction analysis (COBRA)]. Our data suggest that DNMT3B mutations in the ICF syndrome cause lymphogenesis-associated gene dysregulation by indirect effects on gene expression that interfere with normal lymphocyte signaling, maturation and migration.

Cell Line↗
PubMed2002

Promoter-specific activation and demethylation by MBD2/demethylase.

MBD2 is the only member of a family of methyl-CpG-binding proteins that has been reported to be both a transcriptional repressor and a DNA demethylase (dMTase). To understand the apparently contradictory function of MBD2/dMTase, we studied the effects of dMTase overexpression on the activity of various in vitro methylated promoters transiently transfected into HEK293 cells. We found that forced expression of a MBD2/dMTase expression vector (His-dMTase) differentially activated two methylated reporters, pSV40-CAT (the SV40 enhancerless promoter adjacent to the chloramphenicol acetyltransferase (CAT) reporter gene) and pGL2T+I4xTBRE (a region of the p21 promoter next to the luciferase reporter gene), in a time- and dose-dependent manner. His-dMTase increased pSV40-CAT expression by 3-10-fold after 96 h, while pGL2T+I4xTBRE expression was increased by 2-3-fold after only 48 h and did not further increase at 96 h. Gene activation was not universal because no effect was seen with the p19-ARF promoter. We then assessed whether activation might be due to demethylation within the promoter region. Using bisulfite mapping, we found that exogenous expression of His-dMTase induced demethylation at 8 of the 10 CpG sites within the SV40 promoter. The observation that His-dMTase increases the demethylase activity in the cells was also confirmed using an in vitro CpG demethylase assay with a mC32pG oligonucleotide substrate and purified Q-Sepharose fractions from HEK293 cells transfected with His-dMTase or empty pcDNA3.1His vector. We propose that a single protein possessing both repressor and demethylase functions has evolved to coordinate a program that requires suppression of some methylated genes and activation of others.

Base Sequence↗
PubMed2005

Differential DNA methylation of gene promoters in small B-cell lymphomas.

Improved care of patients with small B-cell lymphomas (SBCLs) is likely to result from the ongoing discovery of molecular markers that better define these malignant neoplasms. We identified multiple gene loci whose DNA methylation patterns differed between 3 types of SBCL: B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, and grades I and II follicular lymphoma. This analysis was performed using an oligonucleotide microarray that allowed determination of the DNA methylation status of 156 loci in 38 genes. Combined bisulfite restriction analysis and methylation-specific polymerase chain reaction were used to validate the differential methylation of 6 of these genes. By using non-Hodgkin lymphoma cell lines as models, these genes were examined further for methylation and gene expression relationships. This study illustrates nonrandom epigenetic alterations in SBCLs that seem to preferentially involve lymphomas of germinal center derivation.

DNA Methylation↗
PubMed1997

An efficient process for production of N-acetylneuraminic acid using N-acetylneuraminic acid aldolase.

N-acetyl-D-neuraminic acid (Neu5Ac) aldolase (EC 4.1.3.3) has bee reported for synthesis of Neu5Ac,1-5 but there are no reports of processes which do not have significant drawbacks for large-scale operation. Here, Neu5Ac aldolase from an overexpressing recombinant strain of Escherichia coli has been used to develop an immobilized enzyme process for production of Neu5Ac. The enzyme was immobilized onto Eupergit-C and could be reused many times in the reaction. Base-catalyzed epimerization of N-acetyl-D-glucosamine (GlcNAc) yielded GlcNAc/N-acetyl-D-mannosamine (ManNAc) mixtures (c 4:1) which could be used directly in the aldolase reaction; however, inhibition of the enzyme by GlcNAc limited the concentration of ManNAc which could be used in the reaction by this approach. This necessitated the addition of a large molar excess of pyruvate (five- to seven-fold) to drive the equilibrium over to Neu5Ac; nevertheless, a method has been developed to remove the excess pyruvate effectively by complexation with bisulfite, thus allowing Neu5Ac to be recovered by absorption onto an anion-exchange resin. In a second approach, a method has been developed to enrich GlcNAc/ManNAc mixtures for ManNAc. ManNAc can be used at high concentrations in the reaction, thus obviating the need to use a large molar excess of pyruvate. Neu5Ac can be isolated from such reaction mixtures by a simple crystallization. This work shows the importance of integrated process solutions for the effective scale-up of biotransformation reactions.

1-Propanol↗
PubMed2006

Rab33A: characterization, expression, and suppression by epigenetic modification.

Rab33A, a member of the small GTPase superfamily, is an X-linked gene that is expressed in brain, lymphocytes, and normal melanocytes, but is downregulated in melanoma cells. We demonstrate that in normal melanocytes Rab33A colocalizes with melanosomal proteins and that a constitutively active GTPase mutant suppresses their transport to the melanosomes. In the brain, Rab33A is present throughout the cortex, as well as in the hippocampal CA fields. A survey of melanocytic lesions demonstrated that aberrant downregulation of Rab33A is an early event that is already prevalent in melanocytes of giant congenital nevi. Analyses of bisulfite-modified DNA revealed that Rab33A is regulated by DNA methylation of a specific promoter region proximal to the transcription initiation site, and that suppression of Rab33A in melanoma cells recapitulates normal processes that control silencing of X-linked genes, but not tissue specific gene expression. This information is important for understanding carcinogenesis as well as other aberrant processes because Rab33A may have an important role in disorders involving X-chromosome-linked genes associated with vesicular transport.

Amino Acid Sequence↗
PubMed2001

Diversity of sulfur isotope fractionations by sulfate-reducing prokaryotes.

Batch culture experiments were performed with 32 different sulfate-reducing prokaryotes to explore the diversity in sulfur isotope fractionation during dissimilatory sulfate reduction by pure cultures. The selected strains reflect the phylogenetic and physiologic diversity of presently known sulfate reducers and cover a broad range of natural marine and freshwater habitats. Experimental conditions were designed to achieve optimum growth conditions with respect to electron donors, salinity, temperature, and pH. Under these optimized conditions, experimental fractionation factors ranged from 2.0 to 42.0 per thousand. Salinity, incubation temperature, pH, and phylogeny had no systematic effect on the sulfur isotope fractionation. There was no correlation between isotope fractionation and sulfate reduction rate. The type of dissimilatory bisulfite reductase also had no effect on fractionation. Sulfate reducers that oxidized the carbon source completely to CO2 showed greater fractionations than sulfate reducers that released acetate as the final product of carbon oxidation. Different metabolic pathways and variable regulation of sulfate transport across the cell membrane all potentially affect isotope fractionation. Previous models that explained fractionation only in terms of sulfate reduction rates appear to be oversimplified. The species-specific physiology of each sulfate reducer thus needs to be taken into account to understand the regulation of sulfur isotope fractionation during dissimilatory sulfate reduction.

Culture Media↗
PubMed2004

Methylation-specific oligonucleotide microarray.

The methylation-specific oligonucleotide (MSO) microarray is a high-throughput approach capable of detecting DNA methylation in genes across several CpG sites. Based on the bisulfite modification of DNA that converts unmethylated cytosines to uracil but leaves the 5'methylcytosine intact, the method utilizes short oligonucleotides corresponding to the methylated and unmethylated alleles as probes affixed on solid support and products amplified from bisulfite-treated DNA as targets for hybridization. MSO is suitable for examining a panel of genes across multiple clinical samples. This approach can generate a robust dataset for discovering profiles of gene methylation in cancer with aberrant DNA methylation in the neoplastic genome and widespread hypermethylation in tumor suppressor genes. MSO and other oligonucleotide-based arrays have been applied successfully for analyses of single genes and have been useful in delineating and predicting tumor subgroups using clustering methods. Here we focus on design criteria important to the interrogation of multiple CpG sites across several genes.

DNA Methylation↗
PubMed2000

Loss of estrogen receptor (ER) expression in endometrial tumors is not associated with de novo methylation of the 5' end of the ER gene.

Normal endometrium, an estrogen-responsive tissue, expresses the estrogen receptor (ER) alpha gene. Loss of ER expression, the basis for which is currently unknown, is often seen in advanced stage, poor prognosis endometrial tumors. The ER gene undergoes de novo methylation with high frequency in a wide variety of human tumors, including ER-negative breast cancers. In this study, we used several bisulfite-based detection methods to assess whether loss of ER positivity in endometrial tumors is associated with aberrant methylation of the ER gene. Although extensive methylation of a 600-bp region at the 5' end of the gene was seen in two endometrial carcinoma cell lines, none of the 55 CpGs in this region was methylated in 25 of 26 ER-deficient endometrial carcinomas.

Adult↗
PubMed2002

Epigenetic control of mouse receptor activator of NF-kappa B ligand gene expression.

Receptor activator of NF-kappa B ligand (RANKL) is a membrane-bound signal transducer requisite for differentiation and maintenance of osteoclasts. RANKL expression on stromal/osteoblastic cells is tightly regulated to maintain physiological serum calcium levels and bone mass. These stromal/osteoblastic cells, however, comprise a rather heterogeneous population ranging from immature mesenchymal cells to mature osteoblasts and also respond differently to bone resorptive stimuli. In the mouse coculture system, we also have demonstrated the passage-dependent difference of cultured mouse stromal cells in supporting osteoclastogenesis due to altered RANKL gene expression. To address the issue of what molecular mechanism gives the diversity of RANKL gene expression to stromal/osteoblastic cells, we characterized the mouse RANKL gene promoter that contains two CpG clustering regions; one around the transcription start site, and the other downstream of the vitamin D response element (VDRE). Using earlier- and later-passage mouse ST2 cells, we analyzed the CpG methylation status by sodium bisulfite mapping and found that CpG loci around the transcription start site (-66/+246) were predominantly methylated in later-passage ST2 cells. Moreover, earlier- and later-passage ST2 cells transfected with a RANKL promoter construct showed the same steady-state level of luciferase activity and of the inducible effect of 1,25(OH)(2)D(3). Furthermore, the introduction of methylation to the promoter construct silenced promoter activity. The results suggest that CpG methylation around the transcription start site of the mouse RANKL gene is an important epigenetic event, and that its heterogeneity might cause the diversity of the stromal/osteoblastic cells in RANKL gene expression.

Animals↗
PubMed1985

Point mutations in the P30 domain of the gag gene of Moloney murine leukemia virus.

A series of point mutations in the P30 domain of the Moloney murine leukemia virus gag gene was generated by bisulfite treatment of heteroduplex DNAs containing a single-stranded region in the gag gene. One virus bearing such a mutation exhibited a coordinate defect in gag and pol function, and was similar to previously described deletion mutants with alterations in this gene. One mutant virus displayed a different phenotype: it could assemble virion particles and provide pol function, but the particles were defective in the early stages of infection. The continued concordance of the mutants' failure or ability to both assemble virions and provide pol lends further support to the proposal that similar parts of the gag gene are required for these two processes.

Amino Acid Sequence↗
PubMed2026

Innovative advances and clinical applications of cell-free DNA methylation detection technologies.

Advances in DNA methylation detection technologies have promoted disease-related cell-free DNA (cfDNA) analysis. CfDNA methylation profiling has the potential to serve as a promising clinical tool for early disease diagnosis. However, current detection technologies suffer from high costs, complex operational procedures, and insufficient sensitivity for low-input samples. Moreover, the definitive validation of its clinical value still awaits robust evidence from high-quality confirmatory studies. Therefore, this review begins by mapping the historical evolution of cfDNA methylation, followed by a comparison of the traditional approaches and recent breakthroughs in cfDNA methylation analysis. Specifically, this review systematically examines the two major strategies: the ones based on bisulfite-dependent DNA modification and the bisulfite-free methods, including the techniques for whole-genome methylation profiling and methods targeting specific genomic regions. Additionally, to evaluate the clinical application potential of these methods, this review comprehensively describes the details of these technologies, such as sample input requirements and sensing accuracy in detecting clinical samples. The future development of cfDNA methylation detection will focus on clinical translation, integrating technical innovations with the demands for efficient clinical diagnosis. We believe this review will help researchers select methods tailored to sample availability and clinical applicability.

Humans↗
PubMedDate not supplied

Analyses of promoter hypermethylation for RUNX3 and other tumor suppressor genes in nasopharyngeal carcinoma.

BACKGROUND: Aberrant methylation of cytosine in promoter CpG islands is a recognized contributory process to carcinogenesis. This study explores the methylation profile of RUNX3 in combination with p16, RASSF1A, CDH1 and hMLH1 in nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: Genomic DNA was extracted from 19 fresh frozen NPC biopsies, which were then subjected to bisulfite conversion and methylation-specific PCR for analysis of promoter hypermethylation for the five respective genes. Three cell lines, SNU1, RKO and LS174T, were used as controls. RESULTS: The incidences of promoter methylation were as follows: RUNX3 0/19 (0%), p16 6/19 (32%), RASSF1A 13/19 (68%), CDH1 9/19 (47%) and hMLH1 4/19 (21%). Ninety-five percent of the tumor specimens displayed aberrant methylation in at least one of these genes. No significant correlation between methylation status of these genes and clinical parameters was found. CONCLUSION: Methylation of multiple genes is involved in critical pathways for cancer development in NPC. Promoter hypermethylation for RUNX3 was, however, not present.

Base Sequence↗