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Mammalian preimplantation development is characterized by a number of major events. These potentially involve significant but transient changes in early embryonic gene expression. We have undertaken a meta-analysis of gene expression in mouse preimplantation development using a set of 71 346 expressed sequence tags (EST) derived from 15 non-normalized cDNA libraries. These libraries span seven stages of development from the unfertilized oocyte to the blastocyst stage. EST were clustered using UNIGENE: The 71 346 EST identified 11 483 separate genes, of which 1585 are not found elsewhere in the mouse. Aggregate sets of EST for each of the seven stages were analysed for differences in gene expression using Fisher's exact test. This analysis identified 109 genes that were differentially expressed. Some of these genes were associated with degradation of transcripts at the 1-cell stage whereas other genes underwent increased expression at the blastocyst stage. The set of 11 483 genes identified in mouse preimplantation embryo development provides the starting point for the design of DNA microarrays targeted at early mammalian embryogenesis. By anchoring the analysis of mouse preimplantation development in UniGene, it will be possible to identify homologous genes that are likely to be involved in human preimplantation embryo development.
Mol Hum Reprod 2001 Jun
PMID:Meta-analysis of gene expression in mouse preimplantation embryo development. 1138 9

Progress in the understanding of early mammalian embryo development has been severely hampered by scarcity of study materials. To circumvent such a constraint, we have developed a strategy that involves a combination of in silico mining of new genes from expressed sequence tags (EST) databases and rapid determination of expression profiles of the dbEST-derived genes using a PCR-based assay and a panel of cDNA libraries derived from different developmental stages and somatic tissues. We demonstrate that in a random sample of 49 independent dbEST-derived zinc finger protein genes mined from a mouse embryonic 2-cell cDNA library, more than three-quarters of these genes are novel. Examination of characteristics of the human orthologues derived from these mouse genes reveals that many of them are associated with human malignancies. Expression studies have further led to the identification of three novel genes that are exclusively expressed in mouse embryos before or up to the 8-cell stage. Two of the genes, designated 2czf45 and 2czf48 (2czf for 2-cell zinc finger), are zinc finger protein genes coding for a RBCC protein with a RFP domain and a protein with three C2H2 fingers, respectively. The third gene, designated 2cpoz56, codes for a protein with a POZ domain that is often associated with zinc finger proteins. These three genes are candidate genes for regulatory or other functions in early embryogenesis. The strategy described in this report should generally be applicable to rapid and large-scale mining of other classes of rare genes involved in other biological and pathological processes. Mol. Reprod. Dev. 59:249-255, 2001.
Mol Reprod Dev 2001 Jul
PMID:In silico mining of EST databases for novel pre-implantation embryo-specific zinc finger protein genes. 1142 10

Toxoplasma gondii has a broad host-range including man and a variety of warm-blooded animals. The ability to infect and survive in this wide spectrum of hosts suggests highly evolved mechanisms to handle the harsh environments encountered. Here we show that extracellular tachyzoites are resistant to milligram levels of trypsin and describe the presence of an inhibitor of trypsin associated with the surface of T. gondii, TgTI. TgTI has an estimated molecular mass of 37000 dalton and is encoded by the TgTI-gene which is found at low abundance as an expressed sequence tag (EST) in both the bradyzoite and tachyzoite stages. The inhibitory binding region was found to be in the N-terminus of TgTI where aminoacid-alignment to earlier described protease inhibitors demonstrates 75% similarity. In functional analysis, recombinant TgTI-protein inhibits the activity of trypsin approximately 10 times more efficiently than an inhibitor isolated from soybean. In contrast to other known trypsin inhibitors, TgTI also possesses a predicted membrane-binding region. Polyclonal antibodies raised against recombinant TgTI bind to the surface of the tachyzoite stage as seen both by immunofluorescence and immunoprecipitation of surface labelled parasite proteins. The high survival rate of the parasite in the upper gastrointestinal tract may be enhanced by the presence of the TgTI-molecule.
Mol Biochem Parasitol 2001 Sep 03
PMID:A protease inhibitor associated with the surface of Toxoplasma gondii. 1152 47

The cuticle of parasitic nematodes consists primarily of a network of collagen molecules. The enzyme responsible for collagen maturation is prolyl 4-hydroxylase, making this enzyme a central activity in cuticle biosynthesis and a potentially important chemotherapeutic target. Adult and embryonic Brugia malayi are shown to be susceptible to inhibitors of vertebrate prolyl 4-hydroxylase, with exposed parasites exhibiting pathologies consistent with a disruption in cuticle biosynthesis. A full-length cDNA (Ov-phy-1) encoding a catalytically active alpha-subunit of Onchocerca volvulus prolyl 4-hydroxylase was isolated and characterized. The derived amino acid sequence of Ov-phy-1 encoded a peptide that was most similar to the two Caenorhabditis elegans prolyl 4-hydroxylase homologues and to the isoform II enzymes of vertebrates. Expressed sequence tag (EST) analysis and developmental polymerase chain reaction (PCR) studies demonstrated that Ov-phy-1 was expressed in L3 and adult parasites. The gene encoding the Ov-phy-1 open reading frame contained 11 introns, similar in structure to the gene encoding human prolyl 4-hydroxylase isoform I. Genomic Southern blot, EST and genomic PCR studies demonstrated that the O. volvulus genome contained between three and eight genes closely related to Ov-phy-1. Co-expression of Ov-phy-1 with the O. volvulus homologue of protein disulfide isomerase in a baculovirus system resulted in the production of enzymatically active O. volvulus prolyl 4-hydroxylase. In vitro production of enzymatically active O. volvulus prolyl 4-hydroxylase should facilitate identification of specific inhibitors of the parasite enzyme.
Mol Biochem Parasitol 2001 Sep 03
PMID:Characterization and expression of enzymatically active recombinant filarial prolyl 4-hydroxylase. 1152 51

While there is an ever-increasing amount of information regarding cellulose synthase catalytic subunits (CesA) and their role in the formation of the cell wall, the remainder of the enzymes that synthesize structural cell wall polysaccharides are unknown. The completion of the Arabidopsis genome and the wealth of the sequence information from other plant genome projects provide a rich resource for determining the identity of these enzymes. Arabidopsis contains six families of genes related to cellulose synthase, the cellulose synthase-like (Csl) genes. Our laboratory is taking a multidisciplinary approach to determine the function of the Csl genes, incorporating genomic, genetic and biochemical data. Information from expressed sequence tag (EST) projects has revealed the presence of Csl genes in all plant species with a significant number of ESTs. Certain Csl families appear to be missing from some species. For example, no examples of CslG ESTs have been found in rice or maize. Microarray data and reporter constructs are being used to determine the expression pattern of the CesA and Csl genes in Arabidopsis. Mutations and insertion events have been identified in a majority of the genes in the Arabidopsis CesA superfamily and are being characterized by phenotypic and biochemical analysis. While we cannot yet link the function of any of the Csl genes to their respective products, the expression and localization of these genes is consistent with the expected expression pattern of polysaccharide synthases that contribute to the primary cell wall.
Plant Mol Biol 2001 Sep
PMID:Integrative approaches to determining Csl function. 1155 69

Several important nematode parasites have been found to express members of a gene family variously termed as venom allergen antigen homologue (vah) or Ancylostoma secreted protein (asp). In some cases these products are secreted by infective larval stages and have been suggested to be effective vaccine immunogens. We isolated the corresponding gene from the human filarial nematode, Brugia malayi, by first searching the expressed sequence tag (EST) dataset generated by the Filarial Genome Project and then using gene-specific nondegenerate primers matching the selected gene for PCR, from B. malayi cDNA libraries. We report here the full-length gene sequence, which we have designated as Bm-val-1, for vah/asp-like. The corresponding protein (Bm-VAL-1) contains 232 amino acids in a single homology unit, unlike products from some other species in which there is a tandem repeat. A putative signal sequence is present at the 5' end and there are two potential N-glycosylation sites. Murine antibodies to recombinant Bm-VAL-1 react with a 28 kDa protein in L3 extracts and recombinant Bm-VAL-1 is recognised by murine T cells primed with soluble L3 proteins. Of 82 ESTs corresponding to Bm-val-1, 72 are recorded from the infective larval (L3) stage. However, PCR on the first-strand cDNA from later mammalian stages revealed some expression at most subsequent time points. Over 95% (20/21) of microfilaraemic human filariasis patients are seropositive for antibodies to Bm-VAL-1, with particularly high levels of IgG3 and IgG4 isotypes. The IgG4 subclass may indicate stimulation by adult and/or microfilarial-derived immunogens. The association of Bm-VAL-1 with the infective stage and its recognition by humans exposed to filariasis suggests that further evaluation of this antigen as a vaccine candidate should be performed.
Mol Biochem Parasitol 2001 Nov
PMID:Expression and immune recognition of Brugia malayi VAL-1, a homologue of vespid venom allergens and Ancylostoma secreted proteins. 1170 77

ERCC1 plays an essential role in the nucleotide excision repair (NER) of DNA. We compare 37 kb of sequence from the ERCC1 region on human chromosome 19q13.3 to the orthologous region on mouse chromosome 7. In addition to showing the conserved gene structure between ERCC1, ASE-1, and their murine counterparts, this genomic comparison reveals a highly conserved 497 bp segment found 5 kb upstream of ERCC1 exon 1 that contains a CpG island and previously unidentified "classical" promoter elements. Additional putative regulatory elements are also found within a conserved LINE-1 (long interspersed nuclear element) sequence 800 bp upstream of exon 1 in both human and mouse. Expressed sequence tag (EST) assemblies for human ERCC1 identified numerous splice variants involving exons 1, 2, 3, 7, 8, and 9 that could affect DNA repair efficiencies of ERCC1. A previously undescribed transcript that reads through exon 9 and utilizes the polyadenylation signal of a neighboring Alu element accounts for nearly half of the total splice variants identified in the human EST database. This transcript would theoretically translate to a larger ERCC1 protein product containing a novel C-terminal end. Overall, approximately 18% of publicly available ERCC1 cDNA sequences were determined to be splice variants, while no variants were found in the mouse. The ability to assess novel transcripts and identify candidate regulatory regions demonstrates the potential utility for a catalogue archiving comparative analyses for all genes involved in DNA repair. Our comparative genomic analysis of ERCC1 can be viewed at http://web.uvic.ca/-bioweb/laj.html.
Environ Mol Mutagen 2001
PMID:ERCC1: a comparative genomic perspective. 1174 56

Expressed sequence tag (EST) analysis was applied to identify rice genes involved in defense responses against infection by the blast fungus Magnaporthe grisea and fungal genes involved in growth within the host during a compatible interaction. A total of 511 clones was sequenced from a cDNA library constructed from rice leaves (Oryza sativa cv. Nipponbare) infected with M. grisea strain 70-15 to generate 296 nonredundant ESTs. The sequences of 293 clones (57.3%) significantly matched National Center for Biotechnology Information database entries; 221 showed homologies with previously identified plant genes and 72 with fungal genes. Among the genes with assigned functions, 32.8% were associated with metabolism, 29.4% with cell/organism defense or pathogenicity, and 18.4% with gene/protein expression. cDNAs encoding a type I metallothionein (MTs-1) of rice and a homolog of glucose-repressible gene 1 (GRG1) of Neurospora crassa were the most abundant representatives of plant and fungal genes, comprising 2.9 and 1.6% of the total clones, respectively. The expression patterns of 10 ESTs, five each from rice and M. grisea, were analyzed. Five defense-related genes in rice, including four pathogenesis-related genes and MTs-1, were highly expressed during M. grisea infection. Expression of five stress-inducible or pathogenicity-related genes of the fungus, including two hydrophobin genes, was also induced during growth within the host. Further characterization of the genes represented in this study would be an aid in unraveling the mechanisms of pathogenicity of M. grisea and the defense responses of rice.
Mol Plant Microbe Interact 2001 Nov
PMID:Analysis of genes expressed during rice-Magnaporthe grisea interactions. 1176 34

Prostate cancer is a biologically heterogeneous disease with considerable variation in clinical aggressiveness. The behavior of prostate cancer can be considered a direct or indirect result of aberrant alterations of gene expression in prostate epithelial cells. Identification of the patterns of gene-expression alterations that are related to the aggressiveness of prostate cancers will greatly assist the development of tools for early detection of prostate cancers with poor clinical outcome and identification of targets for future therapeutic intervention. To detect the patterns of gene-expression alterations of prostate cancers, we performed a comprehensive gene-expression analysis on 30 prostate tissues of various levels of invasiveness (ranging from those confined to the organ to distant metastases) and Gleason grades (combined scores 4-9), using the Affymetrix chip set Hu35k (A-D) and U95a. Following three sequential selection screens, we identified 84 largely novel genes and expressed sequence tag (EST) sequences whose expression levels were altered significantly in prostate cancer samples compared with control normal tissues. In addition, the expression levels of a group of 12 genes and EST sequences was found to be altered significantly in aggressive type of prostate cancers but not in organ-confined prostate cancers. Cluster analysis using the 84-gene list showed that the highly aggressive prostate cancers contained gene-expression patterns that were distinct from organ-confined prostate cancers.
Mol Carcinog 2002 Jan
PMID:Gene expression analysis of prostate cancers. 1180 55

GenBank contains 57,151 Expressed Sequence Tags (EST) derived from 11 preimplantation embryo mouse cDNA libraries ranging from the 2-cell embryo to the blastocyst. EST were matched to UniGene clusters to identify a composite set of 11,291 UniGenes. These 11,291 UniGenes were screened using HomoloGene to identify a subset of 3467 mouse UniGenes with matches in at least two other species, one of which was human. Of the 3467 matches, 1542 are for named human proteins. Four of the 11 preimplantation embryo libraries were for blastocysts and contain 22,307 EST. These blastocyst EST generate 5762 UniGenes, of which 2246 have matches in at least two other species. Of the 2246 matches, 1170 are for named human proteins. Comparison of the expression profile of the blastocyst set with a similarly derived set from the mouse oocyte identified a number of transcripts that are significantly up-regulated during preimplantation development. The set of named blastocyst and pre-blastocyst genes complements the similar set published recently for the mouse oocyte. They provide a database for identifying signalling pathways that may play a role in determining cell fate in preimplantation embryo development.
Mol Hum Reprod 2002 Feb
PMID:A set of 1542 mouse blastocyst and pre-blastocyst genes with well-matched human homologues. 1181 18


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