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PubMed2004

Mapping DNA-protein interactions in large genomes by sequence tag analysis of genomic enrichment.

Identifying the chromosomal targets of transcription factors is important for reconstructing the transcriptional regulatory networks underlying global gene expression programs. We have developed an unbiased genomic method called sequence tag analysis of genomic enrichment (STAGE) to identify the direct binding targets of transcription factors in vivo. STAGE is based on high-throughput sequencing of concatemerized tags derived from target DNA enriched by chromatin immunoprecipitation. We first used STAGE in yeast to confirm that RNA polymerase III genes are the most prominent targets of the TATA-box binding protein. We optimized the STAGE protocol and developed analysis methods to allow the identification of transcription factor targets in human cells. We used STAGE to identify several previously unknown binding targets of human transcription factor E2F4 that we independently validated by promoter-specific PCR and microarray hybridization. STAGE provides a means of identifying the chromosomal targets of DNA-associated proteins in any sequenced genome.

Cells, Cultured↗

PubMed2006

Microarray technology in obstetrics and gynecology: a guide for clinicians.

Microarrays can be constructed with dozens to millions of probes on their surface to allow high-throughput analyses of many biologic processes to be performed simultaneously on the same sample. Microarrays are now widely used for gene expression analysis, deoxyribonucleic acid resequencing, single-nucleotide polymorphism genotyping, and comparative genomic hybridization. Microarray technology is accelerating research in many fields and now microarrays are moving into clinical application. This review discusses the emerging role of microarrays in molecular diagnostics, pathogen detection, oncology, and pharmacogenomics.

Chromosome Mapping↗

PubMed2004

Microarray gene expression analysis of the Fob3b obesity QTL identifies positional candidate gene Sqle and perturbed cholesterol and glycolysis pathways.

Obesity-related diseases are poised to become the primary cause of death in developed nations. While a number of monogenic causes of obesity have recently been identified, these are responsible for only a small proportion of human cases of obesity. Quantitative trait locus (QTL) studies using animal models have revealed hundreds of potential loci that affect obesity; however, few have been further analyzed beyond the original QTL scan. We previously mapped four QTL in an F(2) between divergently selected Fat (F) and Lean (L) lines. A QTL of large effect on chromosome 15 (Fob3) was subsequently mapped to a higher resolution into two smaller-effect QTL (Fob3a and Fob3b) using crosses between the F-line and a congenic line containing L-line alleles at the Fob3 QTL region. Here we report the gene expression characterization of Fob3b. Microarray expression analysis using the NIA-NIH 15K cDNA array set containing 14,938 mouse ESTs was employed to identify candidate genes and pathways that are differentially expressed between the F-line and a congenic line containing only the Fob3b QTL (Fob3b-line). Our study suggests squalene epoxidase (Sqle), a cholesterol biosynthesis enzyme, as a strong positional candidate gene for Fob3b. Several other cholesterol biosynthesis pathway genes unlinked to Fob3b were found to be differentially expressed, suggesting that a perturbation of this pathway could be in part responsible for the phenotypic difference between the F-line and Fob3b-line mice.

Animals↗

PubMed2006

The transcriptional regulatory code of eukaryotic cells--insights from genome-wide analysis of chromatin organization and transcription factor binding.

Control of eukaryotic gene expression involves combinatorial interactions between transcription factors and regulatory sequences in the genome. In addition, chromatin structure and modification states play key roles in determining the competence of transcription. The term 'transcriptional regulatory code' has been used to describe the interplay of these events in the complex control of transcription. With the maturation of methods for detecting in vivo protein-DNA interactions on a genome-wide scale, detailed maps of chromatin features and transcription factor localization over entire genomes of eukaryotic cells are enriching our understanding of the properties and nature of this transcriptional regulatory code. The rapidly growing number of maps has revealed the dynamic nature of nucleosome composition and chromatin remodeling at regulatory regions and highlighted some unexpected properties of transcriptional regulatory networks in eukaryotic cells.

Animals↗

PubMed2005

Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart.

BACKGROUND: Down syndrome, caused by trisomic chromosome 21, is the leading genetic cause of mental retardation. Recent studies demonstrated that dosage-dependent increases in chromosome 21 gene expression occur in trisomy 21. However, it is unclear whether the entire transcriptome is disrupted, or whether there is a more restricted increase in the expression of those genes assigned to chromosome 21. Also, the statistical significance of differentially expressed genes in human Down syndrome tissues has not been reported. RESULTS: We measured levels of transcripts in human fetal cerebellum and heart tissues using DNA microarrays and demonstrated a dosage-dependent increase in transcription across different tissue/cell types as a result of trisomy 21. Moreover, by having a larger sample size, combining the data from four different tissue and cell types, and using an ANOVA approach, we identified individual genes with significantly altered expression in trisomy 21, some of which showed this dysregulation in a tissue-specific manner. We validated our microarray data by over 5,600 quantitative real-time PCRs on 28 genes assigned to chromosome 21 and other chromosomes. Gene expression values from chromosome 21, but not from other chromosomes, accurately classified trisomy 21 from euploid samples. Our data also indicated functional groups that might be perturbed in trisomy 21. CONCLUSIONS: In Down syndrome, there is a primary transcriptional effect of disruption of chromosome 21 gene expression, without a pervasive secondary effect on the remaining transcriptome. The identification of dysregulated genes and pathways suggests molecular changes that may underlie the Down syndrome phenotypes.

Astrocytes↗

PubMed2002

Analysis of baseline and cisplatin-inducible gene expression in Fanconi anemia cells using oligonucleotide-based microarrays.

BACKGROUND: Patients with Fanconi anemia (FA) suffer from multiple defects, most notably of the hematological compartment (bone marrow failure), and susceptibility to cancer. Cells from FA patients show increased spontaneous chromosomal damage, which is aggravated by exposure to low concentrations of DNA cross-linking agents such as mitomycin C or cisplatin. Five of the identified FA proteins form a nuclear core complex. However, the molecular function of these proteins remains obscure. METHODS: Oligonucleotide microarrays were used to compare the expression of approximately 12,000 genes from FA cells with matched controls. Expression profiles were studied in lymphoblastoid cell lines derived from three different FA patients, one from the FA-A and two from the FA-C complementation groups. The isogenic control cell lines were obtained by either transfecting the cells with vectors expressing the complementing cDNAs or by using a spontaneous revertant cell line derived from the same patient. In addition, we analyzed expression profiles from two cell line couples at several time points after a 1-hour pulse treatment with a discriminating dose of cisplatin. RESULTS: Analysis of the expression profiles showed differences in expression of a number of genes, many of which have unknown function or are difficult to relate to the FA defect. However, from a selected number of proteins involved in cell cycle regulation, DNA repair and chromatin structure, Western blot analysis showed that p21waf1/Cip1 was significantly upregulated after low dose cisplatin treatment in FA cells specifically (as well as being expressed at elevated levels in untreated FA cells). CONCLUSIONS: The observed increase in expression of p21waf1/Cip1 after treatment of FA cells with crosslinkers suggests that the sustained elevated levels of p21waf1/Cip1 in untreated FA cells detected by Western blot analysis likely reflect increased spontaneous damage in these cells.

Journal Article↗

PubMed2006

Genomic dissection of mucosal immunobiology in the porcine small intestine.

The enteric immune system of swine protects against infectious and noninfectious environmental insults and discriminates ingested nutrients, food, and commensal microflora from pathogenic agents. The molecular and cellular elements of the immune system have been selected over evolutionary time in response to the specific environment of pigs. Thus, models of immune function based on mouse and human need to be applied cautiously in the pig. To better understand how the mucosal immune system of the small intestine accomplishes the conflicting functions of food tolerance and immunity to enteric infection, we used a genomic approach to profile gene expression in the Peyer's patch. More than 40% of mRNA enriched by differential subtraction for Peyer's patch-specific expressed sequences represented genes of unknown function or had no match in GenBank. Microarray analysis and radiation hybrid mapping validated their porcine origin and provided additional insights into putative functions. The abundance of expressed genes of unknown function indicates that a substantial fraction of the immunological and physiological processes of the Peyer's patch remains to be discovered. It further suggests that swine have evolved specialized biochemical and immunological processes in the small intestine. Further elucidation of these processes are expected to provide novel insights into swine enteric mucosal immune function.

Animals↗

PubMed2002

DNA replication joins the revolution: whole-genome views of DNA replication in budding yeast.

Replication origins, which are responsible for initiating the replication of eukaryotic chromosomal DNAs, are spaced at intervals of 40 to 200 kb. Although the sets of proteins that assemble at replication origins during G(1) to form pre-replicative complexes are highly conserved, the structures of replication origins varies from organism to organism. The identification of replication origins has been a labor-intensive task, requiring the analysis of chromosomal DNA replication intermediates. As a result, only a few replication origins have been identified and studied. In a pair of recently published papers, Raghuraman and colleagues and Wyrick, Aparicio and colleagues provide complementary microarray-based approaches to the identification of replication origins. These genome-wide views of DNA replication in Saccharomyces cerevisiae provide new insights into the way that the genome is duplicated and hold promise for the analysis of other genomes.

Biological Evolution↗

PubMed2002

Associations between gene expressions in breast cancer and patient survival.

We analyzed associations between gene expression in breast cancer and patient survival for 8024 genes from a previously published microarray data set. Analysis of survival, by using the logrank test, was performed automatically for each gene. After correcting for multiple testing, we identified 95 genes whose expression was significantly associated with patient survival. The independent prognostic value of the genes ranking the highest in univariate analysis, together with clinical parameters, was assessed by Cox multivariate regression analysis. The P-values from these logrank tests were also mapped to chromosomal positions and compared with previously reported amplicon regions. We used PubGene web tools to identify groups of genes that had co-occurred in the literature and whose expression patterns were associated with survival. Our analyses demonstrate the comprehensiveness of the microarray technology with respect to measuring gene expression and indicate that the technology may be used to screen for potential clinical markers.

Breast Neoplasms↗

PubMed2001

Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma.

Reciprocal chromosomal translocations, which are mediated by errors in immunoglobulin heavy chain (IgH) switch recombination or somatic hypermutation as plasma cells are generated in germinal centers, are present in most multiple myeloma (MM) tumors. These translocations dysregulate an oncogene that is repositioned in proximity to a strong IgH enhancer. There is a promiscuous array of nonrandom chromosomal partners (and oncogenes), with the 3 most frequent partners (11q13 [cyclin D1]; 4p16 [FGFR3 and MMSET]; 16q23 [c-maf]) involved in nearly half of MM tumors. It is now shown that a novel t(6;14)(p21;q32) translocation is present in 1 of 30 MM cell lines and that this cell line uniquely overexpresses cyclin D3. The cloned breakpoint juxtaposes gamma 4 switch sequences with 6p21 sequences that are located about 65 kb centromeric to the cyclin D3 gene. By metaphase chromosome analysis, the t(6;14) (p21;q32) translocation was identified in 6 of 150 (4%) primary MM tumors. Overexpression of cyclin D3 messenger RNA (mRNA) was identified by microarray RNA expression analysis in 3 of 53 additional primary MM tumors, each of which was found to have a t(6;14) translocation breakpoint by interphase fluorescence in situ hybridization analysis. One tumor has a t(6;22)(p21;q11) translocation, so that cyclin D3 is bracketed by the IgL and IgH breakpoints. These results provide the first clear evidence for primary dysregulation of cyclin D3 during tumorigenesis. It is suggested that the initial oncogenic event for most MM tumors is a primary immunoglobulin translocation that dysregulates cyclin D1, cyclin D3, and other oncogenes to provide a proliferative stimulus to postgerminal center plasma cells.

Bone Marrow Cells↗

PubMed2005

Deletions on mouse Yq lead to upregulation of multiple X- and Y-linked transcripts in spermatids.

Deletions on the mouse Y-chromosome long arm (MSYq) lead to teratozoospermia and in severe cases to infertility. We find that the downstream transcriptional changes in the testis resulting from the loss of MSYq-encoded transcripts involve upregulation of multiple X- and Y-linked spermatid-expressed genes, but not related autosomal genes. Therefore, this indicates that in normal males, there is a specific repression of X and Y (gonosomal) transcription in post-meiotic cells, which depends on MSYq-encoded transcripts. Together with the known sex ratio skew in favour of females in the offspring of fertile MSYqdel males, this strongly suggests the existence of an intragenomic conflict between X- and Y-linked genes. Two potential antagonists in this conflict are the X-linked multicopy gene Xmr and its multicopy MSYq-linked relative Sly, which are upregulated and downregulated, respectively, in the testes of MSYqdel males. Xmr is also expressed during meiotic sex chromosome inactivation (MSCI), indicating a link between the MSCI and the MSYq-dependent gonosomal repression in spermatids. We therefore propose that this repression and MSCI itself are evolutionary adaptations to maintain a normal sex ratio in the face of X/Y antagonism.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Two newly characterized germinal center B-cell-associated genes, GCET1 and GCET2, have differential expression in normal and neoplastic B cells.

A group of genes are highly expressed in normal germinal center (GC) B cells and GC B-cell-derived malignancies based on cDNA microarray analysis. Two new genes, GCET1 (germinal center B-cell expressed transcript 1) and GCET2, were cloned from selected expressed sequence tags (IMAGE clone 1334260 and 814622, respectively). GCET1 is located on chromosome 14q32 and has four splicing isoforms, of which the longest one is 1787 bp and encodes a 435-amino acid protein. GCET2 is located on 3q13.13, and the cloned fragment is 3270 bp, which encodes a protein of 178 amino acids. Blast search showed that GCET1 has a highly conserved serine proteinase inhibitor (SERPIN) domain and is located on a chromosomal locus containing seven other SERPIN family members. GCET2 is a likely homologue of the mouse gene M17, a GC-expressed transcript. Analysis of the GCET2 protein sequence indicated that it may be involved in signal transduction in the cytoplasm. Northern blot and real-time polymerase chain reaction analyses confirmed that GCET1 is highly restricted to normal GC B cells and GCB-cell-derived cell lines. Although GCET2 is also a useful marker for normal and neoplastic GC B cells, it has a wider range of expression including immature B and T cells. Real-time polymerase chain reaction assay showed that both GCET1 and GCET2 are preferentially expressed in follicular lymphoma and diffuse large B-cell lymphoma with GC B-cell differentiation, confirming previous microarray gene expression analysis, but neither one is entirely specific. Multiple markers are necessary to differentiate the GCB from the activated B-cell type of diffuse large B-cell lymphoma with a high degree of accuracy.

Amino Acid Sequence↗

PubMed2005

An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the major causes of cancer deaths worldwide. New diagnostic and therapeutic options are needed for more effective and early detection and treatment of this malignancy. We identified 703 genes that are highly expressed in HCC using DNA microarrays, and further characterized them in order to uncover novel tumor markers, oncogenes, and therapeutic targets for HCC. Using Gene Ontology annotations, genes with functions related to cell proliferation and cell cycle, chromatin, repair, and transcription were found to be significantly enriched in this list of highly expressed genes. We also identified a set of genes that encode secreted (e.g. GPC3, LCN2, and DKK1) or membrane-bound proteins (e.g. GPC3, IGSF1, and PSK-1), which may be attractive candidates for the diagnosis of HCC. A significant enrichment of genes highly expressed in HCC was found on chromosomes 1q, 6p, 8q, and 20q, and we also identified chromosomal clusters of genes highly expressed in HCC. The microarray analyses were validated by RT-PCR and PCR. This approach of integrating other biological information with gene expression in the analysis helps select aberrantly expressed genes in HCC that may be further studied for their diagnostic or therapeutic utility.

Biomarkers, Tumor↗

PubMed2005

Response of malignant B lymphocytes to ionizing radiation: gene expression and genotype.

The human malignant B-lymphocyte cell lines Reh and U698 show arrest in G2 phase after ionizing radiation (IR), but only Reh cells arrest in G1 phase and die by apoptosis. We have used cDNA microarrays to measure changes in gene expression at 2, 4 and 6 hr after irradiation of Reh and U698 cells with 0.5 and 4 Gy in order to begin exploring the molecular mechanisms underlying the phenotypic changes. We also investigated whether gene expression changes could be caused by possible aberrations of genes, as measured by comparative genomic hybridization. Reh cells showed upregulation of CDKN1A that likely mediated the G1 arrest. In contrast, U698 cells have impaired function of TP53 protein and no activation of CDKN1A, suppressing the arrest in G1. The G2 arrest in both cell lines was likely due to repression of PLK1 and/or CCNF. IR-induced apoptosis in Reh cells was probably mediated by TP53 and CDKN1A, whereas a high expression level of MCL1, caused by gene amplification, and activation of the NFKB pathway may have suppressed the apoptotic response in U698 cells. Genes suggested to be involved in apoptosis were activated long before this phenotype was detectable and showed the same temporal expression profiles as genes involved in cell cycle arrest. Our results suggest that differences in functionality and/or copy number of several genes involved in IR-regulated pathways contributed to the phenotypic differences between Reh and U698 cells after IR, and that multiple molecular factors control the radiation response of malignant B lymphocytes.

Chromosome Aberrations↗

PubMed2004

4p terminal deletion and 11p subtelomeric duplication detected by genomic microarray in a patient with Wolf-Hirschhorn syndrome and an atypical phenotype.

We report a de novo cryptic 11p duplication found by genomic microarray with a cytogenetically detected 4p deletion. Terminal 4p deletions cause Wolf-Hirschhorn syndrome, but the phenotype probably was modified by the paternally derived 11p duplication. This emphasizes the clinical utility of genomic microarray.

Abnormalities, Multiple↗

PubMed2006

[Microarray-based comparative genomic hybridization in the study of constitutional chromosomal abnormalities].

Chromosomal aberrations are the first cause of mental impairment and dysmorphism. Rearrangements involving large chromosomal segments can be detected by standard chromosome analysis using GTG-banding, but this technique is not suited for the detection of small chromosome abnormalities. Array comparative genomic hybridisation (array-CGH) is a method used to detect segmental DNA copy number alterations. Recently, advances in this technology have enabled high-resolution examination for identifying genetic alterations and copy number variations on a genome-wide scale. This review describes the current genomic array platforms and CGH methodologies and highlights their applications for studying constitutional disease.

Chromosome Disorders↗

PubMed2006

MAMMOT--a set of tools for the design, management and visualization of genomic tiling arrays.

UNLABELLED: The MAMMOT software suite is a collection of Perl and PHP scripts for designing, annotating and visualizing genome tiling arrays to, for example, facilitate studies into the epigenetics of gene regulation. The web design allows rapid experimental data entry from multiple users, and results can easily be shared between groups and individuals. AVAILABILITY: http://www.mammot.org.uk/ CONTACT: e.ryder@gen.cam.ac.uk.

Animals↗

PubMed2002

DNA hypomethylation, cancer, the immunodeficiency, centromeric region instability, facial anomalies syndrome and chromosomal rearrangements.

Inadequate attention has been paid to the frequent and often extensive cancer-associated DNA hypomethylation. This hypomethylation usually includes undermethylation of certain DNA repeats in constitutive heterochromatin, although it is not limited to such sequences. Many cancers display an overall deficiency in the levels of genomic 5-methylcytosine compared to a variety of normal postnatal somatic tissues. The immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome, a rare recessive DNA methyltransferase deficiency disease, results in a small decrease in the extent of global genomic methylation. In ICF, DNA hypomethylation is targeted to the satellite DNA in juxtacentromeric (centromere-adjacent) heterochromatin of chromosomes 1 and 16 (1qh and 16qh), which are prone to rearrangements in ICF lymphoid cells. Also, 1qh and 16qh DNA sequences frequently are hypomethylated in human cancers and rearrangements in their vicinity are overrepresented in cancers. These often lead to chromosome arm imbalances and gene dosage imbalances that could participate in carcinogenesis. Studies of ICF cells suggest that hypomethylation in the normally highly methylated 1qh and 16qh regions predisposes to heterochromatin decondensation in these regions, which in turn leads to elevated levels of rearrangements. Studies of ICF cells also suggest that some of these rearrangements, namely multiradial chromosomes with multiple arms joined in the pericentromeric region, may be unstable intermediates in formation of more stable pericentromeric rearrangements in cancer. Microarray gene expression analysis on ICF and normal lymphoblastoid cell lines suggests that this hypomethylation also may affect gene expression elsewhere in the genome.

Blotting, Southern↗