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PubMed2002

A novel herpes simplex virus type 1 transcript (AL-RNA) antisense to the 5' end of the latency-associated transcript produces a protein in infected rabbits.

Following primary ocular infection, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons of the trigeminal ganglia. Latency-associated transcript (LAT), the only known viral gene abundantly transcribed during HSV-1 neuronal latency, is required for high levels of reactivation. Recently we showed that three different mutants that do not alter the LAT promoter but contain deletions within the 5' end of the primary LAT transcript affect viral virulence (G. C. Perng et al., J. Virol. 75:9018-9028, 2001). In contrast, in LAT-null mutants viral virulence appears unaltered (T. M. Block et al., Virology 192:618-630, 1993; D. C. Bloom et al., J. Virol. 68:1283-1292, 1994; J. M. Hill et al., Virology 174:117-125, 1990; G. C. Perng et al., J. Virol. 68:8045-8055, 1994; F. Sedarati, K. M. Izumi, E. K. Wagner, and J. G. Stevens, J. Virol. 63:4455-4458, 1989). We therefore hypothesized that the 5' end of LAT and/or an as yet unidentified gene that overlaps part of this region is involved in viral virulence. We report here on the discovery and initial characterization of a novel HSV-1 RNA consistent with such a putative gene. The novel RNA was antisense to the 5' end of LAT and was designated AL-RNA (anti-LAT sense RNA). The AL-RNA overlapped the core LAT promoter and the first 158 nucleotides of the 5' end of the primary LAT transcript. AL-RNA was detected in extracts from neuron-like cells (PC-12) infected with wild-type HSV-1 but not in cells infected with a mutant with the AL region deleted. The deletions in each of the above three mutants with altered virulence encompass the 5' end of the AL-RNA, and these mutants cannot transcribe AL. This supports the hypothesis that the AL gene may play a role in viral virulence. Based on comparison to the corresponding genomic sequence, the AL-RNA did not appear to be spliced. The AL-RNA was polyadenylated and contained an open reading frame capable of encoding a protein 56 amino acids in length with a predicted molecular mass of 6.8 kDa. Sera from three of three rabbits infected with wild-type HSV-1 but not sera from any of three rabbits infected with a mutant with the AL-RNA region deleted recognized the Escherichia coli recombinantly expressed AL open reading frame on Western blots. In addition, four of six rabbits infected with wild-type virus developed enzyme-linked immunosorbent assay titers against one or more AL synthetic peptides. These results suggest that an AL protein is produced in vivo.

Amino Acid Sequence↗

PubMed1997

Isolation and characterisation of a linked cluster of genes from Agrobacterium tumefaciens encoding proteins involved in flagellar basal-body structure.

We report the DNA sequence of 7205 bp of the Agrobacterium tumefaciens chromosome. This contains a putative operon encoding homologues of the flagellar rod and associated proteins FlgBCG and FliE, the L and P ring proteins (FlgHI) a possible flagellum-specific export protein FliP, and two proteins of unknown function, FlgA and FliL. Several of these genes have overlapping stop and start codons. Three non-flagellate Tn5-induced mutations map to this operon: fla-11 to the first gene, encoding the rod protein FlgB; fla-15 to flgA; and fla-12 to fliL. A site-specific mutation introduced into the final gene in this cluster, fliP, also resulted in a non-flagellate phenotype. This indicates that the operon is expressed, and that at least FlgB, FlgA, FliL and FliP are required for flagellar assembly in A. tumefaciens. The bulk of this operon is conserved in the same order in Rhizobium meliloti.

Agrobacterium tumefaciens↗

PubMed2004

The transcriptional response to a peroxisome proliferator-activated receptor alpha agonist includes increased expression of proteome maintenance genes.

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARalpha in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARalpha-null mice. Primary hepatocytes from wild-type but not PPARalpha-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat. The livers from intact wild-type but not PPARalpha-null mice were more resistant to damage after carbon tetrachloride treatment. To determine the molecular basis of the protection by PPARalpha, we identified by transcript profiling genes whose expression was altered by a 7-day exposure to WY in wild-type and PPARalpha-null mice. Of the 815 genes regulated by WY in wild-type mice (p < or = 0.001; > or =1.5-fold or < or =-1.5-fold), only two genes were regulated similarly by WY in PPARalpha-null mice. WY increased expression of stress modifier genes that maintain the health of the proteome, including those that prevent protein aggregation (heat stress-inducible chaperones) and eliminate damaged proteins (proteasome components). Although the induction of proteasomal genes significantly overlapped with those regulated by 1,2-dithiole-3-thione, an activator of oxidant-inducible Nrf2, WY increased expression of proteasomal genes independently of Nrf2. Thus, PPARalpha controls the vast majority of gene expression changes after exposure to WY in the mouse liver and protects the liver from oxidant-induced damage, possibly through regulation of a distinct set of proteome maintenance genes.

Animals↗

PubMed1995

Naturally occurring core-gene-defective hepatitis B viruses.

This study was undertaken to determine the prevalence of core-gene-defective hepatitis B virus (HBV) in patients with chronic HBV infection, and the nature and significance of the deletions. PCR was performed on sera from 263 patients with chronic HBV infection. Seventeen (6.5%) patients had smaller band(s) in addition to a band of the expected size. Additional bands were also detected in the follow-up samples from 80% and 3% patients who had respectively, multiple and single bands initially. Six patients were further studied by direct sequencing. Four patients had in-frame deletions leading to loss of codons 79-122 of the core gene. Two patients had identical frameshift deletions of nucleotides 2204-2333 resulting in the loss of the first nine codons of the overlapping P gene. Follow-up samples from three of four patients studied showed deletions identical to those in the initial samples. The persistence of these deletions suggests that they were stable and that they may contribute to the chronicity of infection.

Adult↗

PubMed1995

Mutation of the PAX6 gene in patients with autosomal dominant keratitis.

Autosomal dominant keratitis (ADK) is an eye disorder chiefly characterized by corneal opacification and vascularization and by foveal hypoplasia. Aniridia (shown recently to result from mutations in the PAX6 gene) has overlapping clinical findings and a similar pattern of inheritance with ADK. On the basis of these similarities, we used a candidate-gene approach to investigate whether mutations in the PAX6 gene also result in ADK. Significant linkage was found between two polymorphic loci in the PAX6 region and ADK in a family with 15 affected members in four generations (peak LOD score = 4.45; theta = .00 with D11S914), consistent with PAX6 mutations being responsible for ADK. SSCP analysis and direct sequencing revealed a mutation in the PAX6 exon 11 splice-acceptor site. The predicted consequent incorrect splicing results in truncation of the PAX6 proline-serine-threonine activation domain. The SeyNeu mouse results from a mutation in the Pax-6 exon 10 splice-donor site that produces a PAX6 protein truncated from the same point as occurs in our family with ADK. Therefore, the SeyNeu mouse is an excellent animal model of ADK. The finding that mutations in PAX6 underlie ADK, along with a recent report that mutations in PAX6 also underlie Peters anomaly, implicates PAX6 broadly in human anterior segment malformations.

DNA-Binding Proteins↗

PubMed1994

Identification and overlapping expression of multiple unconventional myosin genes in vertebrate cell types.

Myosin diversity in the human epithelial cell line Caco-2BBe, the porcine epithelial cell line LLC-PK1 (CL-4), human peripheral blood leukocytes, and human liver was analyzed. PCR amplification yielded 8-11 putative myosins (depending on the cDNA source) representing six distinct myosin classes. Analysis of clones obtained by hybridization screening demonstrated that the original PCR products correspond to bona fide myosins, based on the presence of sequences highly conserved in other myosins. RNase protection analysis confirmed mRNA expression of 11 myosins in Caco-2BBe cells. Immunoblot analysis showed that at least 6 myosin immunogens are expressed in Caco-2BBe cells. The results reveal the existence of at least 11 unconventional human myosin genes, most of which are expressed in an overlapping fashion in different cell types. The abundance of myosins suggests that the myosin I vs. myosin II paradigm is inadequate to explain actin-based cellular motility.

Amino Acid Sequence↗

PubMed2006

Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells.

Antiestrogens used for breast cancer (BC) treatment differ among each other for the ability to affect estrogen receptor (ER) activity and thereby inhibit hormone-responsive cell functions and viability. We used high-density cDNA microarrays for a comprehensive definition of the gene pathways affected by 17beta-estradiol (E2), ICI 182,780 (ICI), 4OH-tamoxifen (Tamoxifen), and raloxifene (RAL) in ER-positive ZR-75.1 cells, a suitable model to investigate estrogen and antiestrogen actions in hormone-responsive BC. The expression of 601 genes was significantly affected by E2 in these cells; in silico analysis reveals that 86 among them include one or more potential ER binding site within or near the promoter and that the binding site signatures for E2F-1, NF-Y, and NRF-1 transcription factors are significantly enriched in the promoters of genes induced by estrogen treatment, while those for CAC-binding protein and LF-A1 in those repressed by the hormone, pointing to novel transcriptional effectors of secondary responses to estrogen in BC cells. Interestingly, expression of 176 E2-regulated mRNAs was unaffected by any of the antiestrogens tested, despite the fact that under the same conditions the transcriptional and cell cycle stimulatory activities of ER were inhibited. On the other hand, of 373 antiestrogen-responsive genes identified here, 52 were unresponsive to estrogen and 25% responded specifically to only one of the compounds tested, revealing non-overlapping and clearly distinguishable effects of the different antiestrogens in BC cells. As some of these differences reflect specificities of the mechanism of action of the antiestrogens tested, we propose to exploit this gene set for characterization of novel hormonal antagonists and selective estrogen receptor modulators (SERMs) and as a tool for testing new associations of antiestrogens, more effective against BC.

Breast Neoplasms↗

PubMed1991

A distinct Hox code for the branchial region of the vertebrate head.

The branchial region of the vertebrate head forms through complex interactions involving rhombomeric segments, neural crest and branchial arches. It is though that aspects of their patterning mechanisms are linked and involve Hox-2 genes, whose overlapping and spatially restricted expression domains represent a combinatorial code for generating regional diversity. Vertebrates possess four Hox clusters of Antennapedia class homeobox genes, related to each other by duplication and divergence from a common ancestral complex. In consequence, at equivalent positions in different clusters there are highly related genes known as subfamilies or paralogous groups. As Hox-2 genes cannot fully account for patterning individual rhombomeres, we investigated whether offsets in expression limits of paralogous genes could account for the generation of regional diversity. We report here that, with the exception of the labial subfamily, paralogues show identical expression limits in rhombomeres, cranial ganglia and branchial arches, providing a combinatorial Hox code for the branchial region that seems to be different in organization to that of the trunk.

Alleles↗

PubMed2005

The inactivation of KlNOT4, a Kluyveromyces lactis gene encoding a component of the CCR4-NOT complex, reveals new regulatory functions.

We have isolated the KlNOT4 gene of the yeast Kluyveromyces lactis, which encodes a component of the evolutionarily conserved CCR4-NOT complex. We show that inactivation of the gene leads to pleiotropic defects that were differentially suppressed by the NOT4 gene of S. cerevisiae, indicating that these genes have overlapping, but not identical, functions. K. lactis strains lacking Not4p are defective in fermentation and show reduced transcription of glucose transporter and glycolytic genes, which are phenotypes that are not found in the corresponding mutant of S. cerevisiae. We also show that Not4 proteins control the respiratory pathway in both yeasts, although with some differences. They activate transcription of KlACS2 and KlCYC1, but repress KlICL1, ScICL1, ScACS1, and ScCYC1. Altogether, our results indicate that Not4p is a pivotal factor involved in the regulation of carbon metabolism in yeast.

Amino Acid Sequence↗

PubMed2000

Overlapping roles of two Hox genes and the exd ortholog ceh-20 in diversification of the C. elegans postembryonic mesoderm.

Members of the Hox family of homeoproteins and their cofactors play a central role in pattern formation of all germ layers. During postembryonic development of C. elegans, non-gonadal mesoderm arises from a single mesoblast cell M. Starting in the first larval stage, M divides to produce 14 striated muscles, 16 non-striated muscles, and two non-muscle cells (coelomocytes). We investigated the role of the C. elegans Hox cluster and of the exd ortholog ceh-20 in patterning of the postembryonic mesoderm. By examining the M lineage and its differentiation products in different Hox mutant combinations, we found an essential but overlapping role for two of the Hox cluster genes, lin-39 and mab-5, in diversification of the postembryonic mesoderm. This role of the two Hox gene products required the CEH-20 cofactor. One target of these two Hox genes is the C. elegans twist ortholog hlh-8. Using both in vitro and in vivo assays, we demonstrated that twist is a direct target of Hox activation. We present evidence from mutant phenotypes that twist is not the only target for Hox genes in the M lineage: in particular we show that lin-39 mab-5 double mutants exhibit a more severe M lineage defect than the hlh-8 null mutant.

Animals↗

PubMed1998

cDNA sequence and expression of the mouse alpha1(V) collagen gene (Col5a1).

Several overlapping cDNA clones corresponding to the entire coding sequence of the mouse alpha1(V) collagen gene (Col5a1) were isolated. The conceptual amino acid translation indicated a high degree of sequence identity (94%) with the human alpha1(V) chain. All of the important structures previously noted in the human alpha1(V) chain were also conserved in the mouse chain. The alpha1(V) transcripts were easily detected in mouse embryos as early as 11 days post coitum (d.p.c.). The transcripts were widely distributed in non-cartilaginous and cartilaginous tissues. Finally, we calculated the ratio of transcripts of alpha1(V):alpha2(V):alpha1(XI) in the calvaria and tongue of 18 d.p.c. embryos using the competitive reverse transcription-polymerase chain reaction (RT-PCR) technique. The results raised the possibility that there are at least two different kind of types V/XI collagen heterotrimers in mouse embryonic tissues.

Amino Acid Sequence↗

PubMed1985

Isolation of the human insulin-like growth factor genes: insulin-like growth factor II and insulin genes are contiguous.

Overlapping recombinant clones that encompass the insulin-like growth factor (IGF) I and II genes have been isolated from a human genomic DNA library. Each gene is present once per haploid genome; the IGF-I gene spans greater than 35 kilobase pairs (kbp) and the IGF-II gene is at least 15 kbp. The exon-intron organization of these genes is similar, each having four exons, which is one more than the related insulin gene. Comparison of the restriction endonuclease cleavage maps of the IGF-II and insulin genes, including their flanking regions and hybridization with an IGF-II cDNA probe, revealed that they are adjacent to one another. The IGF-II and insulin genes have the same polarity and are separated by 12.6 kbp of intergenic DNA that includes a dispersed middle repetitive Alu sequence. The order of the genes is 5'-insulin-IGF-II-3'.

Base Sequence↗

PubMed1989

Translational regulation of the lysis gene in RNA bacteriophage fr requires a UUG initiation codon.

Single nucleotide substitutions identify a UUG triplet as the initiation codon of the lysis gene in RNA bacteriophage fr. This initiation codon is non-functional in de novo initiation but is activated by translational termination at the overlapping coat gene. The UUG initiation codon is crucial for gene regulation in the phage, as it excludes uncontrolled access of ribosomes to the start of the lysis gene. Replacement of UUG by either GUG or AUG results in the loss of genetic control of the lysis gene. A model is presented in which initiation factor IF3 proofreads de novo initiation at UUG codons.

Bacteriolysis↗

PubMed2003

Genomewide linkage analysis to presbycusis in the Framingham Heart Study.

OBJECTIVE: To identify chromosomal regions that show evidence of linkage to age-associated hearing impairment (presbycusis) in humans. DESIGN: We evaluated the genetic linkage between quantitative measures from audiometric examinations and markers from a genomewide scan in a population-based sample ascertained without respect to hearing status. PARTICIPANTS: Audiometric examinations were conducted on 2263 original cohort members and 2217 offspring cohort members of the National Heart, Lung, and Blood Institute's Framingham Heart Study. Of these, 1789 individuals were members of 328 extended pedigrees used for linkage analysis. The outcome traits for linkage analysis were pure-tone average at medium (0.5, 1.0, and 2.0 kHz) and low (0.25, 0.5, and 1.0 kHz) frequencies adjusted for cohort, sex, age, age squared, and age cubed. RESULTS: We found heritability (proportion of variance due to genes) of age-adjusted pure-tone average at medium and low frequencies to be 0.38 and 0.31, respectively. Genomewide linkage analysis identified several locations with suggestive evidence of linkage. Of particular interest are the regions 11p (maximum multipoint logarithm of odds [MLOD], 1.57), 11q13.5 (MLOD, 2.10), and 14q (MLOD, 1.55), which overlap with genes known to cause congenital deafness. CONCLUSIONS: There is evidence that genetic and environmental factors contribute to hearing loss in the mature human population. Several of the chromosomal locations identified overlap with loci known to cause congenital hearing loss. Further studies are needed to determine whether the same genes cause presbycusis and congenital hearing loss.

Aged↗

PubMed1989

Mutagenesis by random cloning of an Escherichia coli kanamycin resistance gene into the genome of the cyanobacterium Synechocystis PCC 6803: selection of mutants defective in photosynthesis.

Photosynthetic mutants of the cyanobacterium Synechocystis PCC 6803 were produced by a random cartridge mutagenesis method leading to gene inactivation. This procedure relies on random ligation of an Escherichia coli kanamycin resistance (Kmr) gene to restriction fragments of genomic DNA from the host. Then recombination occurring during transformation promotes integration of the marker gene into the genome of the recipient cells. Several mutants impaired in photosynthesis were obtained by this procedure. All are partially or totally defective in photosystem II activity and some of them also harbour a functionally modified photosystem I. Restriction and recombination data showed that one mutant (AK1) is best explained as an insertion of the Kmr gene into an AvaII restriction site of the gene psbD-1. All others harbour a deletion, ranging from at least 1.15 kb (AK3) to more than 50 kb (AK9), which partly or fully overlaps the genes psbB and/or psbD-1, depending on the mutant. A genetic-physical map of the more than 60 kb region of the cyanobacterial genome harbouring the genes psbB, psbC and psbD-1 was constructed by combining published sequence data on these genes with the results of recombination and restriction mapping.

Chromosome Mapping↗

PubMed1997

Nucleotide sequence and transcriptional analysis of a portion of the bovine herpesvirus genome encoding genes homologous to HSV-1, UL25, UL26 and UL26.5.

We determined the nucleotide sequence of a 3,811 base pair (bp) region of the bovine herpesvirus type-1 (BHV-1) HindIII-A fragment covering map units 0.429-0.456, which contained the HSV-1 homologues of the UL25, UL26 and UL26.5 genes. Sequence overlap was verified with previously published BHV-1 sequences, resulting in contiguous sequence spanning from UL24 to UL27 (encoding glycoprotein B). We found that the UL25 open reading frame (ORF) overlapped that of UL24 by 16 nucleotides, an unexpected feature based on previous herpesvirus sequences. We previously showed that the BHV-1 UL26 and UL26.5 genes encoded proteins that functioned in proteinase and scaffolding activity during capsid assembly, similar to the homologues in herpes simplex virus type-1. Northern blotting was used to map the four major transcripts from this region. As expected from the ORF analysis, the BHV-1 UL25 transcript initiated within the UL24 ORF. The BHV-1 UL24, UL25, UL26 and UL26.5 transcripts all terminated at a common 3'-polyadenylation site and varied significantly in their relative abundance.

Amino Acid Sequence↗

PubMed2005

Bayesian model averaging: development of an improved multi-class, gene selection and classification tool for microarray data.

MOTIVATION: Selecting a small number of relevant genes for accurate classification of samples is essential for the development of diagnostic tests. We present the Bayesian model averaging (BMA) method for gene selection and classification of microarray data. Typical gene selection and classification procedures ignore model uncertainty and use a single set of relevant genes (model) to predict the class. BMA accounts for the uncertainty about the best set to choose by averaging over multiple models (sets of potentially overlapping relevant genes). RESULTS: We have shown that BMA selects smaller numbers of relevant genes (compared with other methods) and achieves a high prediction accuracy on three microarray datasets. Our BMA algorithm is applicable to microarray datasets with any number of classes, and outputs posterior probabilities for the selected genes and models. Our selected models typically consist of only a few genes. The combination of high accuracy, small numbers of genes and posterior probabilities for the predictions should make BMA a powerful tool for developing diagnostics from expression data. AVAILABILITY: The source codes and datasets used are available from our Supplementary website.

Algorithms↗

PubMed1987

Expression and replication of the hepatitis B virus genome under foreign promoter control.

A novel expression system was established that allows expression and propagation of the human hepatitis B virus (HBV) genome in cultured animal cells. An overlength HBV genome encoding the viral pregenomic RNA was put under transcriptional control of the human metallothionein IIA promoter thereby replacing the endogenous HBV core gene promoter. Transient expression of this construct in hepatoma cells resulted in formation of particles indistinguishable from HBV (Dane particles). Uncoupling of the promoter from overlapping HBV genes facilitated a mutational analysis of HBV gene functions. For example, removal of the preC start codon completely prevented HBeAg synthesis whereas formation of HBV-like particles remained unaffected. In addition, overexpression of the core gene led to detection of minor and otherwise undetectable core gene products, including a core/pol fusion protein and larger precursor molecules of the secreted HBeAg.

Cloning, Molecular↗