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PubMed2006

Inactivation of the group A Streptococcus regulator srv results in chromosome wide reduction of transcript levels, and changes in extracellular levels of Sic and SpeB.

Group A Streptococcus is characterized by the ability to cause a diverse number of human infections including pharyngitis, necrotizing fasciitis, toxic shock syndrome, and acute rheumatic fever, yet the regulation of streptococcal genes involved in disease processes and survival in the host is not completely understood. Genome scale analysis has revealed a complex regulatory network including 13 two-component regulatory systems and more than 100 additional putative regulators, the majority of which remain uncharacterized. Among these is the streptococcal regulator of virulence, Srv, the first Group A Streptococcus member of the Crp/Fnr family of transcriptional regulators. Previous work demonstrated that the loss of srv resulted in a significant decrease in Group A Streptococcus virulence. To begin to define the gene products influenced by Srv, we combined microarray and two-dimensional gel electrophoresis analysis. Loss of srv results in a chromosome wide reduction of gene transcription and changes in the production of the extracellular virulence factors Sic (streptococcal inhibitor of complement) and SpeB (cysteine proteinase). Sic levels are reduced in the srv mutant, whereas the extracellular concentration and activity of SpeB is increased. These data link Srv to the increasingly complex GAS regulatory network.

Antigens, Bacterial↗
PubMed2006

Chromosomal and genetic imbalances in synovial sarcoma detected by conventional and microarray comparative genomic hybridization.

PURPOSE: To analyze the relationship between chromosomal instabilities and clinicopathological factors in synovial sarcoma (SS). METHODS: Twenty-two fresh-frozen SS were analyzed by metaphase comparative genomic hybridization (CGH). Additional microarray CGH was performed in 13 cases. RESULTS: Fourteen patients with SYT-SSX1 rearrangements and nine patients with biphasic tumor subtypes had better prognosis than the eight patients with SYT-SSX2 rearrangements and 13 patients with monophasic subtypes, respectively. Gains (average 3.0) were more frequent than losses (average 1.0). Frequent gains were identified on chromosomal regions 2, 6q, 7, 8q, 12, 17q, 18q, and 21q, whereas frequent losses were over-lapped on chromosomes 1p31-p35, 3p, 6q, 16, and 17p. High-level gains were observed on chromosomes 1q21-q31, 7, 8, 12, 17q, 18q, and 21q. Thirteen monophasic and nine biphasic tumors had an average of 5.1 and 2.8 aberrations, respectively. Patients with tumors harboring numerous aberrations (>or=3) had a worse clinical course. Microarray CGH more specifically detected genetic imbalances including gains in MDM2, MSH2, KCNK12, DCC, CDK2, ERBB3, SAS, and CDK4 and losses in HRAS, RASSF1, and CCND1. Gain of SAS was an important prognostic factor of SS. CONCLUSION: We have identified several factors influencing the prognosis of SS patients by metaphase and microarray CGH.

Adolescent↗
PubMed2005

Mapping long-range chromatin organization within the chicken alpha-globin gene domain using oligonucleotide DNA arrays.

We have analyzed the organization of the chicken alpha-globin gene domain using DNA miniarrays and have found two novel chromatin loop attachment regions. We have found a 40-kb loop domain that includes all the alpha-globin genes in cells of erythroid origin. One of the domain borders colocalizes almost exactly with a strong MAR element and with a block of enhancer-blocking elements found earlier at the upstream end of the alpha-globin gene domain. The domain structure was found to be different in a lymphoid cell line DT40. We propose to use the technique of DNA arrays to map the nuclear matrix attachment sites that define the borders of chromosome loop domains. The technique of DNA arrays permits a large number of DNA sequences to be immobilized on a glass or nylon matrix. This may prove useful for mapping chromatin loop positions within the human genome by using a pool of chromatin loop attachment regions as a probe in a hybridization with a DNA chip containing a specific DNA region.

Animals↗
PubMed2005

Dual regulation of genes involved in acetoin biosynthesis and motility/biofilm formation by the virulence activator AphA and the acetate-responsive LysR-type regulator AlsR in Vibrio cholerae.

AphA is a quorum sensing-regulated activator that initiates the virulence cascade in Vibrio cholerae by cooperating with the LysR-type regulator AphB at the tcpPH promoter on the Vibrio pathogenicity island (VPI). To identify the ancestral chromosomal genes in V. cholerae regulated by AphA, we carried out a microarray analysis and show here that AphA influences the expression of 15 genes not associated with the VPI. One set of genes strongly repressed by AphA is involved in the biosynthesis of acetoin, a product synthesized by a variety of bacteria that plays a role in preventing intracellular acidification and which is essential for the viability of V. cholerae in the presence of glucose. Also present in this operon are two putative signal transduction proteins with EAL and GGDEF domains that oppositely influence motility and biofilm formation. Gel mobility shift assays show that AphA binds to a site upstream of the first gene in the acetoin operon. Transcriptional lacZ fusions indicate that at low cell density AphA represses the expression of the acetoin genes up to 15-fold. Voges Proskauer tests confirm that deletion of AphA increases the production of acetoin under non-inducing conditions and also that the LysR-type regulator AlsR divergently transcribed from the operon is required for its production. This is the first report of a specific repressor protein involved in the transcriptional control of acetoin production as well as the co-regulation of these genes with those that influence motility and biofilm formation. The results here provide a model for the dual regulation of these processes by acetate and quorum sensing through AlsR and AphA.

Acetoin↗
PubMed2006

Medical applications of array CGH and the transformation of clinical cytogenetics.

Microarray-based comparative genomic hybridization (array CGH) merges molecular diagnostics with traditional chromosome analysis and is transforming the field of cytogenetics. Prospective studies of individuals with developmental delay and dysmorphic features have demonstrated that array CGH has the ability to detect any genomic imbalance including deletions, duplications, aneuploidies and amplifications. Detection rates for chromosome abnormalities with array CGH range from 5-17% in individuals with normal results from prior routine cytogenetic testing. In addition, copy number variants (CNVs) were identified in all studies. These CNVs may include large-scale variation and can confound the diagnostic interpretations. Although cytogeneticists will require additional training and laboratories must become appropriately equipped, array CGH holds the promise of being the initial diagnostic tool in the identification of visible and submicroscopic chromosome abnormalities in mental retardation and other developmental disabilities.

Chromosome Aberrations↗
PubMed2002

Genome-wide analysis of gene expression in synovial sarcomas using a cDNA microarray.

Among a histologically heterogeneous group of soft tissue sarcomas, synovial sarcoma (SS) is regarded as a "miscellaneous" entity of uncertain origin. Although recent molecular analysis has disclosed involvement of a specific chromosomal translocation in the pathogenesis of SS, its genetic features remain largely unclear. In the work reported here we examined genome-wide gene expression profiles of 13 SS cases and 34 other spindle-cell sarcoma cases by cDNA microarray consisting of 23,040 genes. A hierarchical clustering analysis grouped SS and malignant peripheral nerve sheath tumor into the same category, and these two types of tumor shared expression patterns of numerous genes relating to neural differentiation. Several genes were up-regulated in almost all SS cases, and the presumed functions of known genes among them were related to migration or differentiation of neural crest cells, suggesting the possibility of neuroectodermal origin of SS. Moreover, we identified a set of genes that divided SS cases into two putative subclasses, a feature that may shed light on novel biological aspects of SS in addition to those having to do with epithelial differentiation. These data have provided clues for understanding the origin and tumorigenesis of SS.

Cluster Analysis↗
PubMed2003

Detection of amplified oncogenes by genome DNA microarrays in human primary esophageal squamous cell carcinoma: comparison with conventional comparative genomic hybridization analysis.

Oncogene amplification in 20 surgically resected esophageal squamous cell carcinomas (ESCC) was examined with DNA microarrays that detected 57 oncogenes and two reference DNA. Alterations in DNA copy numbers detected by microarrays were compared to those obtained by conventional comparative genomic hybridization (CGH). Amplification of eight oncogenes (CCND1, FGF3/FGF4, EMS1, SAS, ERBB2, PDGFRA, MYC, and BCL2) was detected by DNA microarrays in 9 of 20 tumors. Although ERBB2 was 23.2 times higher than the control level in one case, the average magnitude of gene amplification was approximately two to four times that of the control level. EMS1, CCND1, and FGF3/FGF4, which are all located on 11q13, were amplified in 7, 5, and 4 of 20 ESCC, respectively, and they were coamplified in 3 tumors. A comparison of genome DNA microarrays and CGH data revealed that although most amplified oncogenes were included in chromosomal regions for which DNA copy number gains were detected by conventional CGH, not all amplified genes on microarrays showed concomitant DNA copy number gains on CGH. In conclusion, microarrays of oncogenes are useful for the comprehensive identification of amplified oncogenes and for analysis of areas of specific amplification within chromosomal regions with DNA copy number increases detected by CGH analysis.

Aged↗
PubMed2002

Expression profiles of 290 ESTs mapped to chromosome 3 in human epithelial ovarian cancer cell lines using DNA expression oligonucleotide microarrays.

We have investigated previously the utility of oligonucleotide expression microarray technology in an analysis of four spontaneously transformed epithelial ovarian cancer (EOC) cell lines, TOV-21G, TOV-81D, OV-90, and TOV-112D. Here, we examine the expression of 290 expressed sequence tags (ESTs) that map to human chromosome 3 in a primary culture derived from normal ovarian surface epithelium (NOSE), NOV-31, and the four spontaneously transformed EOC cell lines. One of these cell lines, OV-90, harbors a deletion of an entire chromosome 3p arm. Whereas the most aggressive cell lines (OV-90, TOV-112D, and TOV-21G) exhibited the highest levels of expression, assessed by the mean of expression values of all ESTs, OV-90 showed the lowest mean of expression of ESTs that map to the 3p arm in comparison with TOV-112D and TOV-21G. This difference in expression profile of 3p ESTs in OV-90 is also reflected in the ratio of expression of ESTs on 3p versus the 3q arm and in that the expression values of ESTs that map to 3p were more often lower than higher in OV-90 in two-way comparisons with NOV-31, TOV-21G, and TOV-112D. The loss of a 3p arm does not affect the pattern of differential expression in analyses based on the range of numeric expression values of each EST or fold differences in expression for each EST in comparison with NOV-31. However, 25 differentially expressed ESTs were identified on the basis of threefold differences in expression values between NOV-31 and any EOC cell line; and six of these ESTs were differentially expressed uniquely in OV-90. The investigation of these ESTs could facilitate the identification of novel chromosome 3 genes implicated in ovarian tumorigenesis.

Chromosome Mapping↗
PubMed2003

Relationship between gene co-expression and probe localization on microarray slides.

BACKGROUND: Microarray technology allows simultaneous measurement of thousands of genes in a single experiment. This is a potentially useful tool for evaluating co-expression of genes and extraction of useful functional and chromosomal structural information about genes. RESULTS: In this work we studied the association between the co-expression of genes, their location on the chromosome and their location on the microarray slides by analyzing a number of eukaryotic expression datasets, derived from the S. cerevisiae, C. elegans, and D. melanogaster. We find that in several different yeast microarray experiments the distribution of the number of gene pairs with correlated expression profiles as a function of chromosomal spacing is peaked at short separations and has two superimposed periodicities. The longer periodicity has a spacing of 22 genes (approximately 42 Kb), and the shorter periodicity is 2 genes (approximately 4 Kb). CONCLUSION: The relative positioning of DNA probes on microarray slides and source plates introduces subtle but significant correlations between pairs of genes. Careful consideration of this spatial artifact is important for analysis of microarray expression data. It is particularly relevant to recent microarray analyses that suggest that co-expressed genes cluster along chromosomes or are spaced by multiples of a fixed number of genes along the chromosome.

Animals↗
PubMed2005

Genomic analysis of Drosophila chromosome underreplication reveals a link between replication control and transcriptional territories.

In Drosophila polytene chromosomes, most late-replicating regions remain underreplicated. A loss-of-function mutant of the suppressor of underreplication [Su(UR)] gene suppresses underreplication (UR), whereas extra copies of this gene enhance the level and number of regions showing UR. By combining DNA microarray analysis with manipulation of the number of Su(UR) gene copies, we achieved genomic-scale molecular identification of 1,036 genes that are arranged in clusters located in 52 UR chromosomal regions. These regions overlap extensively (96%) but are not completely identical with late-replicating regions of mitotically dividing Kc cells in culture. Reanalysis of published gene expression profiles revealed that genomic regions defined by replication properties include clusters of coordinately expressed genes. Genomic regions that are UR in polytene chromosomes and late replicated in Kc cell chromosomes show a particularly common association with transcriptional territories that are expressed in testis/males but not ovary/females or embryos. An attractive hypothesis for future testing is that factors involved in replication control, such as SU(UR), may interact physically with those involved in epigenetic silencing of transcription territories.

Animals↗
PubMed2004

Distinction of acute lymphoblastic leukemia from acute myeloid leukemia through microarray-based DNA methylation analysis.

Patterns of DNA methylation are substantially altered in malignancies compared to normal tissue, with both genome-wide hypomethylation and regional increase of cytosine methylation at dinucleotides of cytosine and guanine, i.e., CpG dinucleotides. While genome-wide hypomethylation renders chromosomes instable, hypermethylation of CpGs in promoter regions is generally associated with transcriptional silencing, e.g., of tumor suppressor genes. To investigate whether disease-specific methylation profiles exist for different entities of acute leukemia, a microarray-based DNA methylation analysis simultaneously assessing 249 CpG dinucleotides originating from 57 genes was employed. Hereby, samples from precursor B-cell acute lymphoblastic leukemia (ALL) could be distinguished from cases of acute myeloid leukemia by virtue of N33, EGR4, CDC2, CCND2, or MOS hypermethylation in ALL.

Acute Disease↗
PubMed2002

Differential expression of TCL1 during pre-B-cell acute lymphoblastic leukemia progression.

Nonrandom, recurring chromosomal translocations are critical events in the pathogenesis of leukemia. The recently identified TEL/AML1 (CBFA2/EVT6) fusion gene occurs as a result of the t(12;21)(p13;q22) in approximately 25% of children with diagnosed pre-B-cell acute lymphoblastic leukemia (PBC-ALL). To identify changes in gene expression patterns that occur during PBC-ALL disease progression, we used cDNA microarrays to compare expressed sequences from the AT-1 and AT-2 cell lines. These cell lines, from the same patient, were established from two distinct stages of PBC-ALL disease progression, namely, first and second relapse. Analysis of both cell lines with spectral karyotying (SKY) revealed an insertion of chromosome 8 into chromosome 5 and a previously undetected translocation in AT-2 involving chromosomes 1 and 17. Hybridization of cDNA microarrays identified the TCL1 transcript as being overexpressed in the AT-2 cell line relative to AT-1. Northern blot analysis showed an eightfold increase of the TCL1 transcript in AT-2 over AT-1 cells. Western blot analysis showed that the TCL1 protein was expressed more than 50-fold higher in AT-2 than AT-1 cells. TCL1 expression was correlated with TEL expression by reintroducing TEL into AT-2 cells and demonstrating that those cells expressing TEL at high levels showed a decreased expression of endogenous TCL1.

Acute Disease↗
PubMed2001

Analysis of MUM1/IRF4 protein expression using tissue microarrays and immunohistochemistry.

The gene encoding MUM1 was characterized as a possible translocation partner in chromosomal abnormalities involving a significant number of multiple myelomas. The overexpression of the MUM1 protein as a result of translocation t(6;14) (p25;q32) identified MUM1 as a putative regulatory molecule involved in B-cell differentiation and tumorigenesis. The expression of MUM1 protein in multiple myelomas supports this hypothesis. In the current study, using tissue microarray technology, we have tested the expression of the MUM1 protein in 1335 human malignancies and normal tissues. Our data show that the MUM1 protein is expressed in a wide spectrum of hematolymphoid neoplasms and in malignant melanomas but is absent in other human tumors. In addition, in tissue microarrays as well as in conventional paraffin sections, MUM1 staining was found to lack specificity in detecting plasmacytic differentiation as compared with two markers, CD138/Syndecan and VS38, commonly used in paraffin immunohistochemistry for detection of plasma cells.

Antibodies, Monoclonal↗
PubMed2006

Identification of novel oligodendroglioma-associated candidate tumor suppressor genes in 1p36 and 19q13 using microarray-based expression profiling.

Loss of heterozygosity (LOH) on chromosomal arms 1p and 19q is the most common genetic alteration in oligodendroglial tumors and associated with response to radio- and chemotherapy as well as favorable prognosis. Using microsatellite analysis, we previously identified the chromosomal regions 1p36.22-p36.31 and 19q13.3, as candidate tumor suppressor gene regions being commonly deleted in these tumors. To identify genes within these regions that are downregulated in oligodendroglial tumors with LOH 1p/19q, we performed cDNA microarray-based RNA expression profiling of 35 gliomas with known allelic status on 1p and 19q, including 7 oligodendrogliomas and 8 diffuse astrocytomas of World Health Organization (WHO) grade II, as well as 14 anaplastic oligodendrogliomas and 6 anaplastic oligoastrocytomas of WHO grade III. The microarrays used for expression profiling carried approximately 7,000 gene-specific cDNAs, with complete coverage of the genes located in 1p36.13-p36.31 and 19q13.2-q13.33. Microarray analysis identified 8 genes from these regions (MGC4399, SRM, ICMT, RPL18, FTL, ZIN, FLJ10781 and DBP), which all showed significantly lower expression in 1p/19q-deleted gliomas when compared to gliomas without 1p/19q losses. Quantitative real-time reverse transcription-PCR analyses were performed for the MGC4399, ICMT and RPL18 genes and confirmed the microarray findings. In addition, we found that the cytosolic phospholipase A2 (PLA2G4C) gene at 19q13.3 demonstrated significantly lower expression in anaplastic oligodendrogliomas (WHO grade III) when compared to well-differentiated oligodendrogliomas (WHO grade II). Taken together, our study provides a set of interesting novel candidate genes that may play important roles in the pathogenesis of oligodendroglial tumors.

Adolescent↗
PubMed2001

Reticulum cell sarcoma of lymph node with mixed dendritic and fibroblastic features.

We report a case of clinically aggressive reticulum cell sarcoma with mixed follicular dendritic cell (FDC) and fibroblastic reticular cell (FRC) features. Histologically, the tumor was confined to lymph nodes occurring as a multifocal epithelioid and spindle cell proliferation with appreciable mitotic rate and numerous admixed non-neoplastic B-cells. Ultrastructural examination revealed elongated cells with prominent nucleoli, interdigitating cell processes and frequent desmosomes. These features are typical of FDC sarcoma. However, immunohistochemical stains showed no expression of antigens characteristic of FDCs, including CD21, CD23 and CD35. Cytogenetic characterization of this tumor, by conventional G-banding and multicolor spectral karyotyping, revealed multiple clonal chromosomal aberrations, including del(X)(p11.4) and add (21)(p11.2). Gene expression analysis by cDNA microarray of RNA obtained from short-term tumor cultures revealed high-level expression of a set of genes (including PDGF receptor-alpha and -beta, certain metalloproteinases, and CD105) that were also highly expressed in cultures of nodal FRC cultured from non-neoplastic lymph nodes. We propose that this tumor represents a nodal sarcoma with intermediate differentiation between FDCs and FRCs. This case adds to the diversity of tumors that may arise from lymph node stroma and supports a possible relationship between the FDC and FRC lineages.

Adult↗
PubMed2003

Recruitment of terminal protein to the ends of Streptomyces linear plasmids and chromosomes by a novel telomere-binding protein essential for linear DNA replication.

Bidirectional replication of Streptomyces linear plasmids and chromosomes from a central origin produces unpaired 3'-leading-strand overhangs at the telomeres of replication intermediates. Filling in of these overhangs leaves a terminal protein attached covalently to the 5' DNA ends of mature replicons. We report here the essential role of a novel 80-kD DNA-binding protein (telomere-associated protein, Tap) in this process. Biochemical studies, yeast two-hybrid analysis, and immunoprecipitation/immunodepletion experiments indicate that Tap binds tightly to specific sequences in 3' overhangs and also interacts with Tpg, bringing Tpg to telomere termini. Using DNA microarrays to analyze the chromosomes of tap mutant bacteria, we demonstrate that survivors of Tap ablation undergo telomere deletion, chromosome circularization, and amplification of subtelomeric DNA. Microarray-based chromosome mapping at single-ORF resolution revealed common endpoints for independent deletions, identified amplified chromosomal ORFs adjacent to these endpoints, and quantified the copy number of these ORFs. Sequence analysis confirmed chromosome circularization and revealed the insertion of adventitious DNA between joined chromosome ends. Our results show that Tap is required for linear DNA replication in Streptomyces and suggest that it functions to recruit and position Tpg at the telomeres of replication intermediates. They also identify hotspots for the telomeric deletions and subtelomeric DNA amplifications that accompany chromosome circularization.

Amino Acid Sequence↗
PubMed2004

The role of molecular studies in lymphoma diagnosis: a review.

Lymphoma classification is based on a multiparametric approach to diagnosis, in which clinical features, morphology, immunophenotype, karyotype and molecular characteristics are important to varying degrees. While in most cases, a diagnosis can be confidently established on the basis of morphology and immunophenotype alone, a small proportion of diagnostically difficult cases will rely on molecular studies to enable a definitive diagnosis. This review discusses the various molecular techniques available including Southern blotting (SB), polymerase chain reaction (PCR), fluorescence in situ hybridisation (FISH)--including multicolour-FISH/spectral karyotyping and comparative genomic hybridisation--and also gene expression profiling using cDNA microarray technology. Emphasis is given to the analysis of antigen receptor gene rearrangements and chromosomal translocations as they relate to lymphoma diagnosis and also in the setting of minimal residual disease (MRD) detection and monitoring. Laboratories performing these tests need to have expertise in these areas of testing, and there is a need for greater standardisation of molecular tests. It is important to know the sensitivity and specificity of each test as well as its limitations and the pitfalls in the interpretation of results. Above all, results of molecular testing should never be considered in isolation, and must always be interpreted in the context of clinical and other laboratory data.

Blotting, Southern↗
PubMed2005

DNA polymerases alpha, delta, and epsilon localize and function together at replication forks in Saccharomyces cerevisiae.

Early in eukaryotic cell cycle, a pre-RC is assembled at each replication origin with ORC, Cdc6, Cdt1 and Mcm2-7 proteins to license the origin for use in the subsequent S phase. Licensed origin must then be activated by S-Cdk and Ddk. At the onset of S phase, RPA is loaded on to the ARS in a reaction stimulated by S-Cdk and Ddk, followed by Cdc45-dependent loading of pol alpha, -delta, and -epsilon. This study examines cell cycle-dependent localization of pol alpha, -delta and -epsilon in Saccharomyces cerevisiae using immuno-histochemical and chromatin immuno-precipitation methods. The results show that pol alpha, -delta, or -epsilon localizes on chromatin as punctate foci at all stages of the cell cycle. However, some foci overlap with or are adjacent to foci pulse-labeled with bromodeoxyuridine during S phase, indicating these are replicating foci. DNA microarray analysis localized pol alpha, -delta, and -epsilon to early firing ARSs on yeast chromosome III and VI at the beginning of S phase. These data collectively suggest that bidirectional replication occurs at specific foci in yeast chromosomes and that pol alpha, -delta, and -epsilon localize and function together at multiple replication forks during S phase.

Cell Cycle↗