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PubMed2001

A genetic analysis of neural progenitor differentiation.

Genetic mechanisms regulating CNS progenitor function and differentiation are not well understood. We have used microarrays derived from a representational difference analysis (RDA) subtraction in a heterogeneous stem cell culture system to systematically study the gene expression patterns of CNS progenitors. This analysis identified both known and novel genes enriched in progenitor cultures. In situ hybridization in a subset of clones demonstrated that many of these genes were expressed preferentially in germinal zones, some showing distinct ventricular or subventricular zone labeling. Several genes were also enriched in hematopoietic stem cells, suggesting an overlap of gene expression in neural and hematopoietic progenitors. This combination of methods demonstrates the power of using custom microarrays derived from RDA-subtracted libraries for both gene discovery and gene expression analysis in the central nervous system.

Animals↗
PubMed2000

Robustness against mutations in genetic networks of yeast.

There are two principal mechanisms that are responsible for the ability of an organism's physiological and developmental processes to compensate for mutations. In the first, genes have overlapping functions, and loss-of-function mutations in one gene will have little phenotypic effect if there are one or more additional genes with similar functions. The second mechanism has its origin in interactions between genes with unrelated functions, and has been documented in metabolic and regulatory gene networks. Here I analyse, on a genome-wide scale, which of these mechanisms of robustness against mutations is more prevalent. I used functional genomics data from the yeast Saccharomyces cerevisiae to test hypotheses related to the following: if gene duplications are mostly responsible for robustness, then a correlation is expected between the similarity of two duplicated genes and the effect of mutations in one of these genes. My results demonstrate that interactions among unrelated genes are the major cause of robustness against mutations. This type of robustness is probably an evolved response of genetic networks to stabilizing selection.

Computational Biology↗
PubMed2003

Homeobox gene expression and mutation in cervical carcinoma cells.

An association between deregulation of homeobox (HOX) gene expression and oncogenic transformation has been recently reported in human tumors. In this study, we investigated HOX gene expression and mutation in cervical carcinoma cells. Using reverse transcription-PCR, 11 human cervical carcinoma cell lines and 14 normal cervical tissue samples were examined for mRNA expression of the 39 class I HOX genes. DNA samples from 11 cell lines were tested for mutations in exons 1 and 2 of the HOXA10 and A13 genes using overlapping primer pairs which also cover intron 1 of these genes. HOXA1, B2, B4, C5, C10 and D13 genes were expressed in 8, 7, 9, 9, 9 and 11 of 11 cervical carcinoma cell lines, respectively, but not in any of the normal cervical tissues. HOXA9, A11, A13, B5, C4, D3 and D9 genes were expressed in all cell lines and normal tissues. In contrast, 13 of 39 HOX genes were silent in all materials examined. Single-strand conformational polymorphism and sequence analysis revealed a C insertion after base 1042 and/or a G to C substitution at base 1113 in intron 1 of the HOXA13 gene in 4 of 11 cell lines, however, neither deletions nor mutations were detected in exons 1 and 2 of the HOX A10 and A13 genes. Our data suggest that the expression of HOXA1, B2, B4, C5, C10 and D13 genes might be involved in the process leading to the transformation of normal cervical cells.

Carcinoma, Squamous Cell↗
PubMed1991

Simian immunodeficiency virus negative factor suppresses the level of viral mRNA in COS cells.

The nef gene is conserved among all human and simian lentiviruses. However, the amino acid similarity between simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 NEF is only 38%. To assess the role of SIV NEF on virus replication and compare its activity with that of its human immunodeficiency virus type 1 counterpart, we examined the activity of an intact nef gene from proviral clone pSIV 102, an isolate from SIV-MAC-251-infected cells. Proviral clone pSIV BA was constructed by introducing a premature termination codon at codon 40 of the nef gene without altering the predicted amino acid sequence of the overlapping env gene. These two clones were transfected into CD4- COS cells, and virus replication was monitored by p27 enzyme-linked immunosorbent assay kits. In seven independent experiments, clone pSIV BA afforded two- to sixfold greater levels of viral antigen compared with those in clone pSIV 102 and two- to sixfold-increased levels of viral mRNAs as indicated with Northern (RNA) blot and S1 nuclease protection analyses. Nuclear run-on assays demonstrated a two- to threefold increased rate of RNA synthesis with nuclei isolated from cells transfected with pSIV BA compared with that from cells transfected with pSIV 102. In contrast, there was no apparent destabilization of SIV mRNAs by NEF, as measured in dactinomycin-treated cells. This study demonstrates that SIV NEF is a negative regulator of virus replication and acts by suppressing the level of mRNA synthesis and accumulation in COS cells.

Amino Acid Sequence↗
PubMed1995

Mutations in RAD27 define a potential link between G1 cyclins and DNA replication.

The yeast Saccharomyces cerevisiae has three G1 cyclin (CLN) genes with overlapping functions. To analyze the functions of the various CLN genes, we examined mutations that result in lethality in conjunction with loss of cln1 and cln2. We have isolated alleles of RAD27/ERC11/YKL510, the yeast homolog of the gene encoding flap endonuclease 1, FEN-1.cln1 cln2 rad27/erc11 cells arrest in S phase; this cell cycle arrest is suppressed by the expression of CLN1 or CLN2 but not by that of CLN3 or the hyperactive CLN3-2. rad27/erc11 mutants are also defective in DNA damage repair, as determined by their increased sensitivity to a DNA-damaging agent, increased mitotic recombination rates, and increased spontaneous mutation rates. Unlike the block in cell cycle progression, these phenotypes are not suppressed by CLN1 or CLN2. CLN1 and CLN2 may activate an RAD27/ERC11-independent pathway specific for DNA synthesis that CLN3 is incapable of activating. Alternatively, CLN1 and CLN2 may be capable of overriding a checkpoint response which otherwise causes cln1 cln2 rad27/erc11 cells to arrest. These results imply that CLN1 and CLN2 have a role in the regulation of DNA replication. Consistent with this, GAL-CLN1 expression in checkpoint-deficient, mec1-1 mutant cells results in both cell death and increased chromosome loss among survivors, suggesting that CLN1 overexpression either activates defective DNA replication or leads to insensitivity to DNA damage.

Checkpoint Kinase 1↗
PubMed1992

The rat LPH gene 5' region: comparative structure with the human gene.

We have determined the sequence of a 2784 bp rat genomic fragment originating from the 5' region of the gene coding for intestinal lactase-phlorizin hydrolase. The fragment overlaps the gene exon 1, part of the intron 1 and the 5'-upstream segment including a TATA-like box. Over 155 bp, the upstream segment shows 72% similarity with the corresponding sequence in human. Far upstream, the rat sequence exhibits a Calcium Responsive Element and putative binding sites for AP2, C/EBP, and CTF/NF. The intron contains a T-rich sequence that may cause DNA helix distortion.

Animals↗
PubMed1998

The interaction of the Vibrio cholerae transcription factors, Fur and IrgB, with the overlapping promoters of two virulence genes, irgA and irgB.

irgA, a virulence gene in Vibrio cholerae, encodes a 77kDa outer membrane protein. irgA expression is activated by irgB, which encodes a LysR-type transcription factor and is divergently transcribed from a promoter overlapping that of irgA. Expression of irgA and irgB is repressed by iron and Fur. A 200bp DNA fragment containing the irgA-irgB intergenic region was inserted between the Escherichia coli phoA and lacZ genes, respectively, to generate operon fusions to the two promoters, and this construct was crossed into the chromosomal lacZ gene of V. cholerae. This DNA fragment was sufficient to produce regulation of irgA-phoA and irgB-lacZ transcription by iron, Fur and IrgB. Purified V. cholerae Fur and IrgB overexpressed in E. coli bound simultaneously to this DNA fragment in gel shift experiments, and footprints of both proteins on the irgA-irgB intergenic region were observed using DNaseI footprinting. The Fur footprint overlapped a Fur box, previously identified by homology with the E. coli Fur box. The position of the IrgB footprint was consistent with activation of irgA transcription and repression of irgB transcription by IrgB. We present a model for the interaction of Fur and IrgB in transcriptional regulation of irgA.

Bacterial Proteins↗
PubMed2006

Extensions to gene set enrichment.

MOTIVATION: Gene Set Enrichment Analysis (GSEA) has been developed recently to capture changes in the expression of pre-defined sets of genes. We propose number of extensions to GSEA, including the use of different statistics to describe the association between genes and phenotypes of interest. We make use of dimension reduction procedures, such as principle component analysis, to identify gene sets with correlated expression. We also address issues that arise when gene sets overlap. RESULTS: Our proposals extend the range of applicability of GSEA and allow for adjustments based on other covariates. We have provided a well-defined procedure to address interpretation issues that can raise when gene sets have substantial overlap. We have shown how standard dimension reduction methods, such as PCA, can be used to help further interpret GSEA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Algorithms↗
PubMed2002

Upstream elements present in the 3'-untranslated region of collagen genes influence the processing efficiency of overlapping polyadenylation signals.

3'-Untranslated regions (UTRs) of genes often contain key regulatory elements involved in gene expression control. A high degree of evolutionary conservation in regions of the 3'-UTR suggests important, conserved elements. In particular, we are interested in those elements involved in regulation of 3' end formation. In addition to canonical sequence elements, auxiliary sequences likely play an important role in determining the polyadenylation efficiency of mammalian pre-mRNAs. We identified highly conserved sequence elements upstream of the AAUAAA in three human collagen genes, COL1A1, COL1A2, and COL2A1, and demonstrate that these upstream sequence elements (USEs) influence polyadenylation efficiency. Mutation of the USEs decreases polyadenylation efficiency both in vitro and in vivo, and inclusion of competitor oligoribonucleotides representing the USEs specifically inhibit polyadenylation. We have also shown that insertion of a USE into a weak polyadenylation signal can enhance 3' end formation. Close inspection of the COL1A2 3'-UTR reveals an unusual feature of two closely spaced, competing polyadenylation signals. Taken together, these data demonstrate that USEs are important auxiliary polyadenylation elements in mammalian genes.

3' Untranslated Regions↗
PubMed1992

Mutations affecting translational coupling between the rep genes of an IncB miniplasmid.

The nature of translational coupling between repB and repA, the overlapping rep genes of the IncB plasmid pMU720, was examined. Mutations in the start codon of the promoter proximal gene, repB, reduced the efficiency of translation of both rep genes. Moreover, there was no independent initiation of repA translation in the absence of repB translation. The position of the repB stop codon was crucial for the efficient expression of repA, with the wild-type positioning being optimal. Translational coupling was found to be totally dependent on the formation of a pseudoknot structure. A model which invokes formation of a pseudoknot to facilitate initiation of repA is proposed.

Bacterial Proteins↗
PubMed2004

In vitro transcription of the Listeria monocytogenes virulence genes inlC and mpl reveals overlapping PrfA-dependent and -independent promoters that are differentially activated by GTP.

Most known virulence genes of Listeria monocytogenes are regulated by the transcriptional factor PrfA. Using our recently established in vitro transcription system, we have studied the PrfA-dependent promoter (PinlC) regulating the expression of the small, secreted internalin C. PrfA-dependent and PrfA-independent transcription is observed starting from PinlC in vitro and in vivo, suggesting the presence of two apparently overlapping promoters both of which use the same -10 box. Although the PrfA-dependent transcription requires, as expected, the PrfA-box, PrfA-independent transcription depends on a -35 box located directly downstream of the PrfA-box. PrfA-independent transcription starts at A, 7 bp downstream of the common -10 box (A7), and is strongly inhibited by PrfA because of the close proximity of the PrfA binding site to the -35 box. PrfA-dependent transcription starts preferentially at G5 but, in the absence of this start nucleotide, alternative start sites at A positions 7 or 8 bp downstream of the -10 box can also be used. The -35 box of the PrfA-independent promoter can be functionally inactivated without affecting PrfA-dependent transcription as long as the distance between the PrfA-box and the -10 box remains fixed to 22 (or 23) bp. Vice versa, the PrfA-box can be deleted without affecting PrfA-independent transcription from PinlC, which is no longer inhibited by PrfA. The PrfA-dependent transcription initiation needs, in contrast to the PrfA-independent one, the presence of a high concentration of GTP (and ATP) but not of CTP and UTP. Overlapping PrfA-dependent and PrfA-independent promoter activity was also demonstrated for the mpl promoter (Pmpl). Again, PrfA-dependent transcription starting at Pmpl is dominant at high GTP concentration and PrfA-independent transcription at low GTP. Here too, the PrfA-dependent and the PrfA-independent promoters share the same -10 box characteristic of SigA-loaded RNA polymerase. High GTP concentration also appears to be necessary for transcription initiation at other PrfA-dependent promoters (Phly, PactA) but not at the PrfA-independent promoter PinlC-m8.

Bacterial Proteins↗
PubMed1996

Genomic organization of the murine CTL lipase gene.

Murine cytotoxic T-lymphocyte (CTL) lipase was originally identified as an IL-4-inducible gene in CD8-positive T cells. To further our understanding of both the function and the regulation of CTL lipase in T cells, we have cloned and characterized the murine gene. Two overlapping phage clones spanning 29 kb contain the entire CTL lipase gene. The exon structure is similar to those characterized for the human and canine pancreatic lipase-related protein 1 genes, with notable differences in the 5' end. Transcripts initiate from a site that matches a consensus for an initiator sequence. Potential cis-regulatory elements in the CTL lipase 5' regulatory region that would confer dual tissue specificity in exocrine pancreas and cytotoxic T lymphocytes are identified. The implications of this promoter organization are discussed.

Animals↗
PubMed1990

DNA sequence analysis of the mitochondrial ND4L-ND5 gene complex from Podospora anserina. Duplication of the ND4L gene within its intron.

A 15 kb region of the 100 kb mitochondrial genome of Podospora anserina has been mapped and sequenced (1 kb = 10(3) base-pairs). The genes for ND4L and ND5 are identified as contiguous genes with overlapping termination and initiation codons. In race A (101 kb) the gene for ND4L (4.3 kb) has a gene duplication within an intron including a second subgroup IC intron. Race s (95 kb) lacks this second gene complex. Each intron has the identical 5' exon boundary. Secondary structure analysis showed that the closest relative of the second intron is the first intron itself. The open reading frames of the two introns are also closely related to each other as well as to their counterpart in the ND4L gene of Neurospora crassa. The 9.9 kb ND5 gene starts immediately at the termination codon of ND4L and is split by two group IB introns, one group IC intron and one group II intron. The group II intron is closely related to other group II introns although its open reading frame sequence similarity with retroviral reverse transcriptase appears to be more divergent. The similarities in secondary structure and open reading frames for these six introns are discussed.

Amino Acid Sequence↗
PubMed2004

Sensitivity of the brain transcriptome to connexin ablation.

Extensive studies on mice with total or partial disruption of either connexin43 (Cx43) or connexin32 (Cx32) have detected only subtle changes in central nervous system structure, growth, development, or function. We have used high density cDNA arrays to analyze the regulation, control, and coordination of the abundances of 7446 distinct transcripts in four brains, each of Cx43 null (K43), Cx43 heterozygous (H43), and Cx32 null (K32) mice as compared to the brains of wildtype (W) mice. The use of multiple samples allowed the determination of the statistical significance of gene regulation. Significantly regulated genes encoded proteins of all functional categories, extending beyond those that might be expected to depend on junctional communication. Moreover, we found a high degree of similarity between genes regulated in the K43 and H43 brains and a remarkable overlap between gene regulation in brains of K43 and K32. The regulated genes in both K43 and H43 brains showed an outstanding inverse coordination with the levels of expression of Cx43 in W brain, indicating that the regulated genes are largely predictable from their co-variance with Cx43 in the wildtype samples. These findings lead to the hypothesis that connexin expression may represent a central node in the regulation of gene expression patterns in brain.

Animals↗
PubMed1984

Structure and organization of the C4 genes.

This 200 000 Mr serum protein is coded for by at least two separate loci, C4A and C4B, which map in the HLA Class III region on chromosome 6 in man. Both loci are highly polymorphic with more than 30 alleles, including null alleles assigned to the two loci. The complete nucleotide sequence of a full length C4A cDNA clone and a substantial part of a C4b cDNA clone has shown class differences which can be used to synthesize nucleotide probes specific for C4A and C4B. Three C4 loci of approximately 16 kilobases each spaced by 10 kilobases have been identified in DNA from one individual and aligned 30 kilobases from the factor B gene by overlapping cloned genomic fragments from a cosmid library. Characterization of these genes by restriction mapping, nucleotide sequence analysis and hybridization with C4A and C4B specific synthetic oligonucleotides show that these genes are very similar.

Alleles↗
PubMed2026

Genome-wide mapping of stress-responsive lncRNA, uc.104, reveals the chromatin-mediated regulation of stress and plasticity-related genes in the hippocampus of chronic restraint rats.

Chronic stress significantly impacts hippocampal function through transcriptional and epigenetic mechanisms. While the roles of lncRNAs in stress-related transcriptional and epigenetic regulation have recently been recognized, their genome-wide functions controlling the transcriptional network remain largely unclear. Evidence indicates that the lncRNA uc.104 is involved in stress responses; however, its genome-wide chromatin interactions and gene regulatory effects are yet to be explored. To examine this, we combined chromatin isolation by RNA purification sequencing (ChIRP-seq) and RNA sequencing (RNA-seq) in the hippocampus from handled control and chronic restraint stress (CRS) rats. ChIRP-seq identified 6,664 uc.104 binding peaks under CRS, including 6,517 enriched and 149 reduced. Many peaks were mapped to intronic and promoter-proximal regions of protein-coding genes. Integration of ChIRP-seq with RNA-seq data revealed 1,839 differentially expressed genes associated with uc.104 binding sites, with 106 high-confidence overlaps. Several genes (Gabra3, Htr7, Irs1, Gpr37, Clu, Hspa1b, Ppp3r2, Nfasc, Pcdhac2, and Cysltr2) identified as regulatory targets of uc.104, have been directly implicated in stress responses, synaptic plasticity, and neuroinflammation. Gene ontology and Synapse GO (SynGO) analyses revealed significant enrichment for processes involving dendritic spine formation, synapse organization, and pre- and postsynaptic signaling. Protein-protein interaction analysis identified hub genes, including EGFR, CDC42, IGF1R, CTNNB1, CALM1, CALM3, POLR2A, MDM2, TBP, and CSNK1E, several of which have been linked to stress-responsive pathways. Together, our findings reveal that uc.104 binding to chromatin near stress- and synapse-related genes may act as a regulator of stress-responsive transcriptional networks in the hippocampus. By linking uc.104 occupancy to stress and synaptic responsive genes, this study highlights uc.104 as a potential mediator of stress-induced hippocampal malfunctions.

Animals↗
PubMed2005

Gene expression signatures of seven individual human embryonic stem cell lines.

Identification of molecular components that define a pluripotent human embryonic stem cell (hESC) provides the basis for understanding the molecular mechanisms regulating the maintenance of pluripotency and induction of differentiation. We compared the gene expression profiles of seven genetically independent hESC lines with those of nonlineage-differentiated cells derived from each line. A total of 8,464 transcripts were expressed in all hESC lines. More than 45% of them have no yet-known biological function, which indicates that a high number of unknown factors contribute to hESC pluripotency. Among these 8,464 transcripts, 280 genes were specific for hESCs and 219 genes were more than twofold differentially expressed in all hESC lines compared with nonlineage-differentiated cells. They represent genes implicated in the maintenance of pluripotency and those involved in early differentiation. The chromosomal distribution of these hESC-enriched genes showed over-representation in chromosome 19 and under-representation in chromosome 18. Although the overall gene expression profiles of the seven hESC lines were markedly similar, each line also had a subset of differentially expressed genes reflecting their genetic variation and possibly preferential differentiation potential. Limited overlap between gene expression profiles illustrates the importance of cross-validation of results between different ESC lines.

Cell Differentiation↗
PubMed1986

A map of the hCG beta-LH beta gene cluster.

The beta-subunit of human chorionic gonadotropin (hCG beta) is reportedly encoded by as many as seven non-allelic genes or pseudogenes. Previous studies have identified a cluster of three hCG beta gene copies and the single-copy lutropin-beta subunit (LH beta) gene, but overlap of this cluster with two additional pairs of hCG beta genes has not been demonstrated, despite the isolation of 18 genomic clones. To define the number and organization of non-allelic hCG beta gene copies, genomic Southern blot analyses were performed using hCG beta cDNA and gene-flanking unique-sequence probes. The data show the linear arrangement of six genes (or pseudogenes) and show that the hCG beta-IH beta gene cluster is present in a single 58-kilobase EcoRI fragment. Our map of the cluster indicates which of the cloned hCG beta genes reflect somatic genotypes rather than recombinant artifacts and will thus permit investigation of factors regulating expression during gestation.

Bacteriophage lambda↗