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PubMed2001

Concept of immunomics: a new frontier in the battle for gene function?

At the beginning of the 21st century, biology will try to address the function of a large number of new genes. From the perspective of technologies applied today to functional genomics, this task appears to be more complex than the effort invested in the sequencing of the human genome. Conceptually, a high-throughput approach permitting correlation between newly discovered genes and functional properties of their protein products has yet to be developed. To address relationships between tens of thousands of genes and their cognate proteins, novel interdisciplinary technologies need to emerge. In this paper, a new idea of immunomics is presented and an experimental strategy is outlined to circumvent some of the restrictions associated with methodologies currently in use. It is proposed that cloned segments of genomic DNA are used for genetic immunization to obtain a large collection of antibodies, and to generate microarrays of these antibodies for tracing differentially expressed cellular proteins.

Animals↗
PubMed1994

Setting limits on homeotic gene function: restraint of Sex combs reduced activity by teashirt and other homeotic genes.

Each of the homeotic genes of the HOM or HOX complexes is expressed in a limited domain along the anterior-posterior axis. Each homeotic protein directs the formation of characteristic structures, such as wings or ribs. In flies, when a heat shock-inducible homeotic gene is used to produce a homeotic protein in all cells of the embryo, only some cells respond by altering their fates. We have identified genes that limit where the homeotic gene Sex combs reduced (Scr) can affect cell fates in the Drosophila embryo. In the abdominal cuticle Scr is prevented from inducing prothoracic structures by the three bithorax complex (BX-C) homeotic genes. However, two of the BX-C homeotic genes, Ultrabithorax (Ubx) and abdominal-A (abd-A), have no effect on the ability of Scr to direct the formation of salivary glands. Instead, salivary gland induction by Scr is limited in the trunk by the homeotic gene teashirt (tsh) and in the last abdominal segment by the third BX-C gene, Abdominal-B (AbdB). Therefore, spatial restrictions on homeotic gene activity differ between tissues and result both from the regulation of homeotic gene transcription and from restraints on where homeotic proteins can function.

Animals↗
PubMed1987

Cytoplasmic effect on gene function in Xenopus laevis.

The pigmentation gene of Xenopus laevis is dominant and that of albino aP mutant recessive. Heterologous haploid hybrids are produced by UV inactivation of the egg nuclei during second polar body formation in the mutant sperm-fertilized Xenopus eggs. During development of these hybrids, melanin appeared in the eye and melanophores in the skin at stages comparable to those of the wild type, but much earlier than in the albino mutant. The number and intensity of pigment cells are intermediate between the black Xenopus and albino mutant. While a number of pigment cells remain in the hybrids, those in the albino eventually degenerate. Therefore, the development and maintenance of pigmentation in heterologous hybrids are contributed by Xenopus cytoplasm. Tadpole tail-tips were squashed and stained for chromosome counting. The results show that Xenopus and mutants are diploid (36 chromosomes) and heterologous haploid hybrids have 18 chromosomes.

Animals↗
PubMed1979

Adherent cell function in murine T lymphocyte antigen recognition. III. A macrophage-mediated immune response gene function in the mouse.

The I region of the MHC appears to control antigen-specific macrophage-T lymphocyte interaction. The immune response to antigens such as Gl phi 9 are under control of two distinct I subregions, I-A and I-E/I-C. We have asked in a macrophage-dependent, antigen-specific murine T cell proliferation assay whether either or both gene products need be expressed in the antigen-presenting cells. We find that both Ir-Gl phi 9 alpha and beta genes must be expressed and function in the antigen-presenting cell.

Animals↗
PubMed2005

A combined approach exploring gene function based on worm-human orthology.

BACKGROUND: Many aspects of the nematode Caenorhabditis elegans biology are conserved between invertebrates and vertebrates establishing this particular organism as an excellent genetic model. Because of its small size, large populations and self-fertilization of the hermaphrodite, functional predictions carried out by genetic modifications as well as RNAi screens, can be rapidly tested. RESULTS: In order to explore the function of a set of C. elegans genes of unknown function, as well as their potential functional roles in the human genome, we performed a phylogenetic analysis to select the most probable worm orthologs. A total of 13 C. elegans genes were subjected to down-regulation via RNAi and characterization of expression profiles using GFP strains. Previously unknown distinct expression patterns were observed for four of the analyzed genes, as well as four visible RNAi phenotypes. In addition, subcellular protein over-expression profiles of the human orthologs for seven out of the thirteen genes using human cells were also analyzed. CONCLUSION: By combining a whole-organism approach using C. elegans with complementary experimental work done on human cell lines, this analysis extends currently available information on the selected set of genes.

Animals↗
PubMed1989

Chromosomal protein HMG-14. Identification, characterization, and chromosome localization of a functional gene from the large human multigene family.

The human HMG-14 multigene family is one of the largest retropseudogene families known. To identify and isolate a functional human HMG-14 gene, genomic clones, selected with the cDNA, were screened with a set of 6 oligonucleotides. A single genomic clone was isolated suggesting that the human genome contains few, and perhaps only one, functional genes. An 8882-base pair (bp) genomic clone containing the complete, 6804-bp-long human gene together with 850 bp 5' to the start of transcription and 1228 bp 3' to the end of transcription was sequenced. The gene is comprised of 6 exons ranging in size from 30 to 839 bp, two of which code for the entire DNA binding site of the protein, and has several features typical of "housekeeping" genes. Using human-rodent somatic cell hybrids, the HMG-14 gene was localized to human chromosome 21. A restriction fragment length polymorphism, useful for further analysis and mapping, has been detected. The present article, which describes the first isolation and characterization of a gene coding for chromosomal protein HMG-14, indicates that genes coding for HMG-14 and HMG-17 may share several distinctive characteristics. Comparison with the human and chicken HMG-17 genes reveals that all contain 6 exons, that all have exons of similar size, that all have 5' regions highly enriched in GC residues and that all have features typical of housekeeping genes.

Animals↗
PubMed2000

A large database of chicken bursal ESTs as a resource for the analysis of vertebrate gene function.

Chicken B cells create their immunoglobulin repertoire within the Bursa of Fabricius by gene conversion. The high homologous recombination activity is shared by the bursal B-cell-derived DT40 cell line, which integrates transfected DNA constructs at high rates into its endogenous loci. Targeted integration in DT40 is used frequently to analyze the function of genes by gene disruption. In this paper, we describe a large database of >7000 expressed sequence tags (ESTs) from bursal lymphocytes that should be a valuable resource for the identification of gene disruption targets in DT40. ESTs of interest can be recognized easily by online or keyword searches. Because the database reflects the gene expression profile of bursal lymphocytes, it provides valuable hints as to which genes might be involved in B-cell-specific processes related to immunoglobulin repertoire formation, signal transduction, transcription, and apoptosis. This large collection of chicken ESTs will also be useful for gene expression studies and comparative gene mapping within the chicken genome project. Details of the bursal EST sequencing project and access to database search forms can be found on the DT40 web site (http://genetics.hpi.uni-hamburg.de/dt40.html).

Animals↗
PubMed1995

Implementing transgenic and embryonic stem cell technology to study gene expression, cell-cell interactions and gene function.

This review highlights the use of transgenic mice and gene targeting in the study of reproduction, pituitary gene expression, and cell lineage. Since 1980 numerous applications of transgenic animal technology have been reported. Altered phenotypes resulting from transgene expression demonstrated that introduced genes can exert profound effects on animal physiology. Transgenic mice have been important for the study of hormonal and developmental control of gene expression because gene expression in whole animals often requires more DNA sequence information than is necessary for expression in cell cultures. This point is illustrated by studies of pituitary glycoprotein hormone alpha- and beta-subunit gene expression (Kendall et al., Mol Endocrinol 1994; in press [1]. Transgenic mice have also been invaluable for producing animal models of cancer and other diseases and testing the efficacy of gene therapy. In addition, cell-cell interactions and cell lineage relationships have been explored by cell-specific expression of toxin genes in transgenic mice. Recent studies suggest that attenuated and inducible toxins hold promise for future transgene ablation experiments. Since 1987, embryonic stem (ES) cell technology has been used to create numerous mouse strains with targeted gene alterations, contributing enormously to our understanding of the functional importance of individual genes. For example, the unexpected development of gonadal tumors in mice with a targeted disruption of the inhibin gene revealed a potential role for inhibin as a tumor suppressor (Matzuk et al., Nature 1992:360: 313-319 [2]. The transgenic and ES cell technologies will undoubtedly continue to expand our understanding and challenge our paradigms in reproductive biology.

Animals↗
PubMed2004

Phydbac2: improved inference of gene function using interactive phylogenomic profiling and chromosomal location analysis.

Phydbac (phylogenomic display of bacterial genes) implemented a method of phylogenomic profiling using a distance measure based on normalized BLAST scores. This method was able to increase the predictive power of phylogenomic profiling by about 25% when compared to the classical approach based on Hamming distances. Here we present a major extension of Phydbac (named here Phydbac2), that extends both the concept and the functionality of the original web-service. While phylogenomic profiles remain the central focus of Phydbac2, it now integrates chromosomal proximity and gene fusion analyses as two additional non-similarity-based indicators for inferring pairwise gene functional relationships. Moreover, all presently available (January 2004) fully sequenced bacterial genomes and those of three lower eukaryotes are now included in the profiling process, thus increasing the initial number of reference genomes (71 in Phydbac) to 150 in Phydbac2. Using the KEGG metabolic pathway database as a benchmark, we show that the predictive power of Phydbac2 is improved by 27% over the previous version. This gain is accounted for on one hand, by the increased number of reference genomes (11%) and on the other hand, as a result of including chromosomal proximity into the distance measure (16%). The expanded functionality of Phydbac2 now allows the user to query more than 50 different genomes, including at least one member of each major bacterial group, most major pathogens and potential bio-terrorism agents. The search for co-evolving genes based on consensus profiles from multiple organisms, the display of Phydbac2 profiles side by side with COG information, the inclusion of KEGG metabolic pathway maps the production of chromosomal proximity maps, and the possibility of collecting and processing results from different Phydbac queries in a common shopping cart are the main new features of Phydbac2. The Phydbac2 web server is available at http://igs-server.cnrs-mrs.fr/phydbac/.

Artificial Gene Fusion↗
PubMed2006

Gene function and expression level influence the insertion/fixation dynamics of distinct transposon families in mammalian introns.

BACKGROUND: Transposable elements (TEs) represent more than 45% of the human and mouse genomes. Both parasitic and mutualistic features have been shown to apply to the host-TE relationship but a comprehensive scenario of the forces driving TE fixation within mammalian genes is still missing. RESULTS: We show that intronic multispecies conserved sequences (MCSs) have been affecting TE integration frequency over time. We verify that a selective economizing pressure has been acting on TEs to decrease their frequency in highly expressed genes. After correcting for GC content, MCS density and intron size, we identified TE-enriched and TE-depleted gene categories. In addition to developmental regulators and transcription factors, TE-depleted regions encompass loci that might require subtle regulation of transcript levels or precise activation timing, such as growth factors, cytokines, hormones, and genes involved in the immune response. The latter, despite having reduced frequencies of most TE types, are significantly enriched in mammalian-wide interspersed repeats (MIRs). Analysis of orthologous genes indicated that MIR over-representation also occurs in dog and opossum immune response genes, suggesting, given the partially independent origin of MIR sequences in eutheria and metatheria, the evolutionary conservation of a specific function for MIRs located in these loci. Consistently, the core MIR sequence is over-represented in defense response genes compared to the background intronic frequency. CONCLUSION: Our data indicate that gene function, expression level, and sequence conservation influence TE insertion/fixation in mammalian introns. Moreover, we provide the first report showing that a specific TE family is evolutionarily associated with a gene function category.

Animals↗
PubMed1999

Prediction of gene function by genome-scale expression analysis: prostate cancer-associated genes.

We wish to identify genes associated with disease. To do so, we look for novel genes whose expression patterns mimic those of known disease-associated genes, using a method we call Guilt-by-Association (GBA), on the basis of a combinatoric measure of association. Using GBA, we have examined the expression of 40,000 human genes in 522 cDNA libraries, and have discovered several hundred previously unidentified genes associated with cancer, inflammation, steroid-synthesis, insulin-synthesis, neurotransmitter processing, matrix remodeling, and other disease processes. The majority of the genes thus discovered show no sequence similarity to known genes, and thus could not have been identified by homology searches. We present here an example of the discovery of eight genes associated with prostate cancer. Of the 40,000 most-abundant human genes, these 8 are the most closely linked to the known diagnostic genes, and thus are prime targets for pharmaceutical research.

Gene Expression Profiling↗
PubMed2001

Chloromethane utilization gene cluster from Hyphomicrobium chloromethanicum strain CM2(T) and development of functional gene probes to detect halomethane-degrading bacteria.

Hyphomicrobium chloromethanicum CM2(T), an aerobic methylotrophic member of the alpha subclass of the class proteobacteria, can grow with chloromethane as the sole carbon and energy source. H. chloromethanicum possesses an inducible enzyme system for utilization of chloromethane, in which two polypeptides (67-kDa CmuA and 35-kDa CmuB) are expressed. Previously, four genes, cmuA, cmuB, cmuC, and purU, were shown to be essential for growth of Methylobacterium chloromethanicum on chloromethane. The cmuA and cmuB genes were used as probes to identify homologs in H. chloromethanicum. A cmu gene cluster (9.5 kb) in H. chloromethanicum contained 10 open reading frames: folD (partial), pduX, orf153, orf207, orf225, cmuB, cmuC, cmuA, fmdB, and paaE (partial). CmuA from H. chloromethanicum (67 kDa) showed high identity to CmuA from M. chloromethanicum and contains an N-terminal methyltransferase domain and a C-terminal corrinoid-binding domain. CmuB from H. chloromethanicum is related to a family of methyl transfer proteins and to the CmuB methyltransferase from M. chloromethanicum. CmuC from H. chloromethanicum shows identity to CmuC from M. chloromethanicum and is a putative methyltransferase. folD codes for a methylene-tetrahydrofolate cyclohydrolase, which may be involved in the C(1) transfer pathway for carbon assimilation and CO(2) production, and paaE codes for a putative redox active protein. Molecular analyses and some preliminary biochemical data indicated that the chloromethane utilization pathway in H. chloromethanicum is similar to the corrinoid-dependent methyl transfer system in M. chloromethanicum. PCR primers were developed for successful amplification of cmuA genes from newly isolated chloromethane utilizers and enrichment cultures.

Amino Acid Sequence↗
PubMed1993

RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development.

We describe a system to evaluate the function of lymphocyte-specific and generally expressed genes in the differentiation and/or function of lymphocytes. RAG-2 (recombination-activating gene 2)-deficient mice have no mature B and T lymphocytes due to the inability to initiate VDJ recombination. Blastocysts from RAG-2-deficient mice generate animals with no mature B and T cells following implantation into foster mothers. However, injection of normal ES cells into RAG-2-deficient blastocysts leads to the generation of somatic chimeras with mature B and T cells all of which derive from the injected ES cells (referred to as RAG-2-deficient blastocyst complementation). Complementation of RAG-2-deficient blastocysts with mutant ES cells heterozygous for a targeted mutation that deletes all immunoglobulin heavy-chain joining (JH) gene segments (JH+/-) also leads to generation of chimeras with normal B and T cells. However, complementation with ES cells homozygous for the JH mutation (JH-/-) generates animals with normal T cells but no B cells, due to a block in B-cell development at a very early stage. Transfection of a functionally assembled mu heavy-chain gene into the JH-/- ES cells prior to blastocyst injection rescues the JH-/- mutation and allows the generation of both mature T and mature B cells. The rescued B cells express IgM but not IgD and respond normally to bacterial lipopolysaccharide stimulation by proliferating and by secreting IgM.

Animals↗
PubMed2002

Genetic complexity of cellulose synthase a gene function in Arabidopsis embryogenesis.

The products of the cellulose synthase A (CESA) gene family are thought to function as isoforms of the cellulose synthase catalytic subunit, but for most CESA genes, the exact role in plant growth is still unknown. Assessing the function of individual CESA genes will require the identification of the null-mutant phenotypes and of the gene expression profiles for each gene. Here, we report that only four of 10 CESA genes, CESA1, CESA2, CESA3, and CESA9 are significantly expressed in the Arabidopsis embryo. We further identified two new mutations in the RADIALLY SWOLLEN1 (RSW1/CESA1) gene of Arabidopsis that obstruct organized growth in both shoot and root and interfere with cell division and cell expansion already in embryogenesis. One mutation is expected to completely abolish the enzymatic activity of RSW1(CESA1) because it eliminated one of three conserved Asp residues, which are considered essential for beta-glycosyltransferase activity. In this presumed null mutant, primary cell walls are still being formed, but are thin, highly undulated, and frequently interrupted. From the heart-stage onward, cell elongation in the embryo axis is severely impaired, and cell width is disproportionally increased. In the embryo, CESA1, CESA2, CESA3, and CESA9 are expressed in largely overlapping domains and may act cooperatively in higher order complexes. The embryonic phenotype of the presumed rsw1 null mutant indicates that the RSW1(CESA1) product has a critical, nonredundant function, but is nevertheless not strictly required for primary cell wall formation.

Amino Acid Sequence↗
PubMed1994

The daughterless gene functions together with Notch and Delta in the control of ovarian follicle development in Drosophila.

The daughterless (da) gene in Drosophila encodes a broadly expressed transcriptional regulator whose specific functions in the control of sex determination and neurogenesis have been extensively examined. We describe here a third major developmental role for this regulatory gene: follicle formation during oogenesis. A survey of da RNA and protein distribution during oogenesis reveals a multiphasic expression pattern that includes both germline and soma. Whereas the germline expression reflects da's role in progeny sex determination, the somatic ovary expression of da correlates with the gene's role during egg chamber morphogenesis. Severe, but viable, hypomorphic da mutant genotypes exhibit dramatic defects during oogenesis, including aberrantly defined follicles and loss of interfollicular stalks. The follicular defects observed in da mutant ovaries are qualitatively very similar to those described in Notch (N) or Delta (Dl) mutant ovaries. Moreover, in the ovary da- alleles exhibit dominant synergistic interactions with N or Dl mutations. We propose that all three of these genes function in the same regulatory pathway to control follicle formation.

Animals↗
PubMed2026

Generation of spCAS9 expressing human mesenchymal stem cell line to study gene function during osteoblast differentiation.

Human bone marrow-derived stromal cells (hMSCs) are a great resource for studying how genes influence cell fate and differentiation into various cell types like osteoblasts, adipocytes, and chondrocytes, among other cell types. However, genetic manipulation of primary hMSCs has been challenging due to their short lifespan and cellular senescence after limited passaging. Their low and unstable transfection efficiency also complicates gene delivery or inactivation, hindering long-term functional studies. The limited lifespan has been effectively solved by immortalizing hMSCs with telomerase reverse transcriptase (hMSCs-TERT). The use of these cells is ideal for functional studies of osteoblast and adipocyte differentiation through genetic manipulation, providing a stable and reliable model. Here, we have engineered a stable CAS9 expressing hMSC-TERT cell line (hMSC-TERTCAS9) via lentiviral transduction. The constitutive expression of spCas9 enables efficient and reproducible gene editing. We demonstrate the potential of these hMSC-TERTCAS9 cells for generating gene disruptions using plasmid delivery of guide RNAs as a fast and efficient strategy for targeted genome editing. The edited cells can be sorted and expanded as single cells to obtain homogenous clonal cell lines with mono- as well as bi-allelic gene deletions, a crucial step for producing reliable experimental results. We further validate this cell line as a powerful tool for studying gene function during hMSC proliferation and differentiation, providing 3 distinct examples of its utility. Through the generation of indels, single-cell sorting, and clonal selection, we have efficiently inactivated the vitamin D receptor and created both larger (256 nucleotides) gene disruptions in Forkhead box protein O1 and precise removals of a small genomic sequence (73 nucleotides) coding for microRNA MIR675. This novel hMSC-TERTCAS9 cell line represents a significant advancement, offering a stable, efficient, and versatile platform for advanced genetic studies, high-throughput screening, and the creation of reliable cellular disease models.

CRISPR-Cas9↗
PubMed2005

Evolutionary conservation of Ceratitis capitata transformer gene function.

Transformer functions as a binary switch gene in the sex determination and sexual differentiation of Drosophila melanogaster and Ceratitis capitata, two insect species that separated nearly 100 million years ago. The TRA protein is required for female differentiation of XX individuals, while XY individuals express smaller, presumably nonfunctional TRA peptides and consequently develop into adult males. In both species, tra confers female sexual identity through a well-conserved double-sex gene. However, unlike Drosophila tra, which is regulated by the upstream Sex-lethal gene, Ceratitis tra itself is likely to control a feedback loop that ensures the maintenance of the female sexual state. The putative CcTRA protein shares a very low degree of sequence identity with the TRA proteins from Drosophila species. However, in this study we show that a female-specific Ceratitis Cctra cDNA encoding the putative full-length CcTRA protein is able to support the female somatic and germline sexual differentiation of D. melanogaster XX; tra mutant adults. Although highly divergent, CcTRA can functionally substitute for DmTRA and induce the female-specific expression of both Dmdsx and Dmfru genes. These data demonstrate the unusual plasticity of the TRA protein that retains a conserved function despite the high evolutionary rate. We suggest that transformer plays an important role in providing a molecular basis for the variety of sex-determining systems seen among insects.

Animals↗
PubMed1999

The murine Bin1 gene functions early in myogenesis and defines a new region of synteny between mouse chromosome 18 and human chromosome 2.

We cloned and functionally characterized the murine Bin1 gene as a first step to investigate its physiological roles in differentiation, apoptosis, and tumorigenesis. The exon-intron organization of the >/=55-kb gene is similar to that of the human gene. Consistent with a role for Bin1 in apoptosis, the promoter included a functional consensus motif for activation by NF-kappaB, an important regulator of cell death. A muscle regulatory module defined in the human promoter that includes a consensus recognition site for myoD family proteins was not conserved in the mouse promoter. However, Bin1 is upregulated in embryonic development by E10.5 in myotomes, the progenitors of skeletal muscle, supporting a role in myogenesis and suggesting that the mouse and human genes may be controlled somewhat differently during development. In C2C12 myoblasts antisense Bin1 prevents induction of the cell cycle kinase inhibitor p21WAF1, suggesting that it acts at an early time during the muscle differentiation program. Interspecific mouse backcross mapping located the Bin1 locus between Mep1b and Apc on chromosome 18. Since the human gene was mapped previously to chromosome 2q14, the location of Bin1 defines a previously unrecognized region of synteny between human chromosome 2 and mouse chromosome 18.

Adaptor Proteins, Signal Transducing↗