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PubMed2005

Overlapping gene expression in fetal mouse intestine development and human colorectal cancer.

Pathways relevant to cancer are well known to overlap with fetal development, as reflected in reactivation of embryonic genes in tumors. However, molecular evidence for this notion has gathered in piecemeal fashion, and systematic approaches have rarely been applied to gauge the extent and global characteristics of the overlap in gene expression between developing tissues and cancer. The fraction of genes that is expressed aberrantly in a given cancer and also developmental in primary function is unknown, and the tissue specificity of recapitulated gene expression remains unexplored. We developed a statistical method to relate expression profiles from human colon cancer and diverse nonintestinal tumors to transcripts that decline in expression with epithelial differentiation in the fetal mouse gut. For genes that are overexpressed in colon cancer, we computed 8% to 19% likelihood that they were expressed transiently during epithelial morphogenesis in intestine development. Among genes dysregulated in other tumors, the corresponding likelihood fell between 1% and 6%. Similarly, low probabilities were obtained when we compared genes not overexpressed in colon cancer with transcriptional profiles in intestine organogenesis. Genes that increase after fetal gut epithelial differentiation were not differentially represented between cancerous and normal colon. Our findings systematically characterize the global extent and tissue specificity of developmental expression programs in colorectal cancer and illustrate the use of such an approach to identify candidate biomarkers and therapeutic targets.

Animals↗
PubMed2003

A transcriptionally active human type II gonadotropin-releasing hormone receptor gene homolog overlaps two genes in the antisense orientation on chromosome 1q.12.

GnRH-II peptide hormone exhibits complete sequence conservation across vertebrate species, including man. Type-II GnRH receptor genes have been characterized recently in nonhuman primates, but the human receptor gene homolog contains a frameshift, a premature stop codon (UGA), and a 3' overlap of the RBM8A gene on chromosome 1q.12. A retrotransposed pseudogene, RBM8B, retains partial receptor sequence. In this study, bioinformatics show that the human receptor gene promoter overlaps the peroxisomal protein 11-beta gene promoter and the premature UGA is positionally conserved in chimpanzee. A CGA [arginine (Arg)] occurs in porcine DNA, but UGA is shifted one codon to the 5' direction in bovine DNA, suggesting independent evolution of premature stop codons. In contrast to marmoset tissue RNA, exon- and strand-specific probes are required to distinguish differently spliced human receptor gene transcripts in cell lines (HP75, IMR-32). RBM8B is not transcribed. Sequencing of cDNAs for spliced receptor mRNAs showed no evidence for alteration of the premature UGA by RNA editing, but alternative splicing circumvents the frameshift to encode a two-membrane-domain protein before this UGA. A stem-loop motif resembling a selenocysteine insertion sequence and a potential alternative translation initiation site might enable expression of further proteins involved in interactions within the GnRH system.

Adenoma↗
PubMed1999

OTC and AUL1, two convergent and overlapping genes in the nuclear genome of Arabidopsis thaliana.

In contrast to bacterial, fungal and vertebrate ornithine transcarbamylases (OTCs; EC 2.1.3.3), very little is known about the enzyme in plants. We report here the isolation of a T-DNA-tagged mutant displaying sensitivity to ornithine, whose characterization has allowed for the identification of several complementary and genomic DNA clones encoding the OTC and auxilin-like 1 (AUL1) proteins of the crucifer Arabidopsis thaliana. Transcript mapping revealed that at least 22 bp within the OTC-AUL1 intercoding region are transcribed from both strands, which makes this one of the rarely described cases of convergent and overlapping transcription units in the nuclear genome of a multicellular eukaryote. Transcription of the OTC gene was shown to be ubiquitous in aerial organs of adult plants, whereas that of AUL1 was obscured by the existence of a putative second copy of the gene. The OTC-AUL1 locus maps at the bottom of chromosome 1.

Adaptor Proteins, Vesicular Transport↗
PubMed1998

Divergently transcribed overlapping genes expressed in liver and kidney and located in the 11p15.5 imprinted domain.

Human chromosomal band 11p15.5 has been shown to contain genes involved in the development of several pediatric and adult tumors and in Beckwith-Wiedemann syndrome (BWS). Overlapping P1 artificial chromosome clones from this region have been used as templates for genomic sequencing in an effort to identify candidate genes for these disorders. PowerBLAST identified several matches with expressed sequence tags (ESTs) from fetal brain and liver cDNA libraries. Northern blot analysis indicated that two of the genes identified by these ESTs encode transcripts of 1-1.5 kb with predominant expression in fetal and adult liver and kidney. With RT-PCR and RACE, full-length transcripts were isolated for these two genes, with the largest open reading frames encoding putative proteins of 253 and 424 amino acids. Database comparison of the predicted amino acid sequence of the larger transcript indicated homology to integral membrane organic cation transporters; hence, we designate this gene ORCTL2 (organic cation transporter-like 2). An expressed sequence polymorphism provided evidence that the ORCTL2 gene exhibits "leaky" imprinting in both human fetal kidney and human fetal liver. The mouse orthologue (Orctl2) was identified, and a similar polymorphism was used to demonstrate maternal-specific expression of this gene in fetal liver from interspecific F1 mice. The predicted protein of the smaller gene showed no significant similarity in the database. Northern and RACE analyses suggest that this gene may have multiple transcription start sites. Determination of the genomic structure in humans indicated that the 5'-end of this transcript overlaps in divergent orientation with the first two exons of ORCTL2, suggesting a possible role for antisense regulation of one gene by the other. We, therefore, provisionally name this second transcript ORCTL2S (ORCTL2-antisense). The expression patterns of these genes and the imprinted expression of ORCTL2 are suggestive of a possible role in the development of Wilms tumor (WT) and hepatoblastoma. Although SSCP analysis of 62 WT samples and 10 BWS patients did not result in the identification of any mutations in ORCTL2 or ORCTL2S, it will be important to examine their expression pattern in tumors and BWS patients, since epigenetic alteration at these loci may play a role in the etiology of these diseases.

Amino Acid Sequence↗
PubMed1995

Sequences promoting the transcription of the human XA gene overlapping P450c21A correctly predict the presence of a novel, adrenal-specific, truncated form of tenascin-X.

A compact region in the human class III major histocompatibility locus contains the human genes for the fourth component of human complement (C4) and steroid 21-hydroxylase (P450c21) in one transcriptional orientation, while the gene for the extracellular matrix protein tenascin-X (TN-X) overlaps the last exon of P450c21 on the opposite strand of DNA in the opposite transcriptional orientation. This complex locus is duplicated into A and B loci, so that the organization is 5'-C4A-21A-XA-C4B-21B-XB-3'. Although this duplication event truncated the 65-kb X(B) gene to a 4.5-kb XA gene, the XA gene is transcriptionally active in the adrenal cortex. To examine the basis of the tissue-specific expression of XA and C4B, we cloned the 1763-bp region that lies between the cap sites for XA and C4B and analyzed its promoter activity in both the XA and the C4 orientations. Powerful, liver-specific sequences lie within the first 75 to 138 bp from the C4B cap site, and weaker elements lie within 128 bp of the XA cap site that function in both liver and adrenal cells. Because these 128 bp upstream from the XA cap site are perfectly preserved in the XB gene encoding TN-X, we sought to determine whether a transcript similar to XA arises within the XB gene. RNase protection assays, cDNA cloning, and RT/PCR show that adrenal cells contain a novel transcript, termed short XB (XB-S), which has the same open reading frame as TN-X.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1983

Sendai virus contains overlapping genes expressed from a single mRNA.

The mRNA coding for the Sendai virus P and C proteins was located on the viral genome using cloned DNA and the relevant regions of the DNA were sequenced. The nucleotide sequence revealed two overlapping open reading frames that could code for proteins of 568 and 204 amino acids. Primer extension and S1 nuclease mapping studies detected only a single 1.894 kb mRNA from this region. Hybrid arrest of translation studies using restriction fragments verified the overlapping nature of these genes. Sequence homologies at the beginning of three Sendai virus cistrons suggest that these genes may have arisen by duplication from a common ancestor, possibly an influenza-like virus gene.

Base Sequence↗
PubMed1990

Pseudorabies virus immediate-early gene overlaps with an oppositely oriented open reading frame: characterization of their promoter and enhancer regions.

The immediate-early (IE) gene of pseudorabies virus (PRV) has recently been sequenced for two virus strains. To investigate IE gene regulation and to examine the genome segment reported to encode latency-related transcripts in opposite polarity to the IE gene, sequence analysis has been extended by 5 kb from each end of the IE gene. The IE promoter (P1) was found to be more complex than previously recognized: it consisted of nine imperfect repeats, each containing five to six different consensus elements for transcription factor binding. A second promoter (P2) was discovered downstream of the IE gene. It contained numerous octamer consensus sequences (ATGCAAAT) and recognition sites for transcription factor Sp1; specific binding of nuclear proteins to four Sp1 sites was detected. An open reading frame (ORF3) bordering on P2 was identified, oriented antiparallel to the IE gene. Potential enhancer elements (E3 and E4) were isolated by the enhancer trap technique. Linked to P1 and a CAT indicator gene, E3 acted as an enhancer and E4 as a silencer. The PRV IE gene product repressed transcription from its own promoter and activated the SV40 early promoter. The transactivating virion protein Vmw65 of HSV1 had an opposite effect on these promoters.

Base Sequence↗
PubMed1996

A human protective protein gene partially overlaps the gene encoding phospholipid transfer protein on the complementary strand of DNA.

The entire human protective protein gene has been cloned, and structural analysis revealed that the gene spans 7.5kb and comprises 15 exons. Furthermore, it partially overlaps on the opposite strand with the gene encoding phospholipid transfer protein. This region of DNA on chromosome 20 appears to encode two distinct mRNAs expressing defined functional products, and the mRNAs overlap by 58 nucleotides at their 3'-untranslated ends.

Alternative Splicing↗
PubMed1989

Overlapping genes in a yeast double-stranded RNA virus.

The Saccharomyces cerevisiae viruses have a large viral double-stranded RNA which encodes the major viral capsid polypeptide. We have previously shown that this RNA (L1) also encodes a putative viral RNA-dependent RNA polymerase (D. F. Pietras, M. E. Diamond, and J. A. Bruenn, Nucleic Acids Res., 16:6226, 1988). The organization and expression of the viral genome is similar to that of the gag-pol region of the retroviruses. The complete sequence of L1 demonstrates two large open reading frames on the plus strand which overlap by 129 bases. The first is the gene for the capsid polypeptide, and the second is the gene for the putative RNA polymerase. One of the products of in vitro translation of the denatured viral double-stranded RNA is a polypeptide of the size expected of a capsid-polymerase fusion protein, resulting from a -1 frameshift within the overlapping region. A polypeptide of the size expected for a capsid-polymerase fusion product was found in virions, and it was recognized in Western blots (immunoblots) by antibodies to a synthetic peptide derived from the predicted polymerase sequence.

Base Sequence↗
PubMed1983

Nucleotide sequence for the catalytic domain of colicin E3 and its immunity protein. Evidence for a third gene overlapping colicin.

We have determined the nucleotide sequence of a segment of Co1E3 DNA coding for the carboxyl-terminal, catalytic peptide of colicin E3 and for the immunity protein. The end of the colicin E3 gene is separated from the beginning of the immunity gene by a nine-basepair intercistronic region, suggesting the two genes are expressed as a single transcriptional unit. The immunity gene is expressed, however, in E. coli strains containing Co1E3-pBR322 hybrid plasmids deleted for the 5'-end of the colicin gene. The DNA sequence also contains an unexpected open reading frame (ORF). This ORF is contained within the colicin gene and is in the +1 reading frame with respect to that gene. Plasmids containing the ORF, directed the synthesis of an 11 kilodalton protein in a cell-free, transcription-translation system.

Amino Acid Sequence↗
PubMed1994

New overlapping gene encoded by the cucumber mosaic virus genome.

Cucumber mosaic virus (CMV) contains three genomic RNAs (RNAs 1, 2, and 3) and a subgenomic RNA (RNA 4), a shared feature of the Bromoviridae family which includes cucumoviruses, bromoviruses, alfalfa mosaic virus, and ilarviruses. We describe in this paper the molecular characterization of a novel subgenomic RNA of the Q strain of CMV (Q-CMV), RNA 4A, which was first reported in 1973 (K. W. C. Peden and R. H. Symons, Virology 53, 487-492, 1973). RNA 4A is 682 nucleotides and is identical in sequence to the 3'-terminal 682 nucleotides of RNA 2. RNA 4A encodes a small open reading frame (ORF) of 100 codons, which, in RNA 2, overlaps the C-terminal portion of the major 2a gene; thus it is likely that RNA 4A functions as the mRNA for the in vivo expression of the ORF, called ORF 2b. Polyclonal antibodies raised against a 2b fusion protein expressed in Escherichia coli specifically detected the 2b gene product in Q-CMV-infected cucumber plants by Western immunoblotting. Examination of published viral RNA sequences revealed the conservation of ORF 2b in all of the four other cucumoviruses sequenced to date; however, it is absent from the rest of the Bromoviridae. We suggest that the proposed ORF 2b may be expressed in other cucumoviruses, most likely via 4A-like subgenomic RNAs, and that the predicted gene product may have a unique functional role in the infection process of cucumoviruses.

Amino Acid Sequence↗
PubMed1995

A negative regulatory element in the promoter region of the rat alpha 2A-adrenergic receptor gene overlaps an SP1 consensus binding site.

Three subtypes of alpha 2-adrenergic receptors (alpha 2A, alpha 2B and alpha 2C) have been described that differ in their primary sequence and tissue-specific expression and are encoded by three distinct genes. Previous work has shown that the human alpha 2A-adrenergic receptor gene promoter consists of a TATA-box (TATAAA), palindromic sequence (CCCACGTGGG) and GC-box (GGGGCGG) motif. Sequence analysis of the putative promoter region of the rat alpha 2A-adrenergic receptor gene showed that these promoter regions are conserved in their sequence and relative location. We analysed the transcriptional activity of these regions using RINm5F, a rat insulinoma cell line that expresses the endogenous alpha 2A-adrenergic receptor gene. These results showed that the region from -484 to -92 has a negative effect on transcription, as deletion of this region in alpha 2A-adrenergic receptor gene-chloramphenicol acetyltransferase reporter constructs increased reporter gene activity. This region included the GC-box sequence which is a consensus binding site for the nuclear factor SP1, which is a positive activator of transcription. Gel-mobility-shift assays and supershift assays with an antibody that recognizes SP1 showed binding of the SP1 nuclear factor as well as other nuclear factors to this GC-box region. Additional nuclear factors bind to the downstream palindromic region. We suggest that positive- and negative-acting nuclear factors contribute to the activity of the alpha 2-adrenergic receptor promoter.

Animals↗
PubMed1982

Overlapping genes in the heat-labile enterotoxin operon originating from Escherichia coli human strain.

We have determined the nucleotide sequence at the distal end of the heat-labile enterotoxin subunit A (LT-A) gene (toxA) originating from human enterotoxigenic Escherichia coli. The sequenced region covers the entire LT-A2 region and a part of the LT-A1 region. In confirming our previous prediction based on product analysis of clones toxA regions, the data suggest the overlapping of the distal end (5'-TTA TGA) of toxA with the proximal end (5'-ATG AAT) of the LT subunit B gene (toxB), in the sequences 5'-TTATGAAT. Some additional characteristics of the LT operon as well as of the products are discussed.

Amino Acid Sequence↗
PubMed1993

Control of start codon choice on a plant viral RNA encoding overlapping genes.

The signals that control initiation of translation in plants are not well understood. To dissect some of these signals, we used a plant viral mRNA on which protein synthesis initiates at two out-of-frame start codons. On the large subgenomic RNA (sgRNA1) of barley yellow dwarf virus-PAV serotype, the coat protein (CP) and overlapping 17K open reading frames (ORFs) are translated beginning at the first and second AUG codons, respectively. The roles of bases at positions -3 and +4 relative to the AUG codons in efficiency of translation initiation were investigated by translation of sgRNA1 mutants in a cell-free extract and by expression of a reporter gene from mutant sgRNA1 leaders in protoplasts. The effects of mutations that disrupted and restored secondary structure encompassing the CP AUG independently of, and in combination with, changes to bases -3 and +4 were also examined. Partial digestion of the 5' end of the sgRNA1 leader with structure-sensitive nucleases gave products that were consistent with the predicted secondary structure. Secondary structure had an overall inhibitory effect on translation of both ORFs. In general, the "Kozak rules" of start codon preference predominate in determining start codon choice. Unexpectedly, for a given CP AUG sequence context, changes that decreased initiation at the downstream 17K AUG also reduced initiation at the CP AUG. To explain this observation, we propose a new model in which pausing of the ribosome at the second AUG allows increased initiation at the first AUG. This detailed analysis of the roles of primary and secondary structure in controlling translation initiation should be of value for understanding expression of any plant gene and in the design of artificial constructs.

Animals↗
PubMed1982

A viable simian virus 40 variant with a deletion in the overlapping genes for virion proteins VP1, VP2 and VP3.

Nucleotide sequence analysis was used to determine the exact location of a deletion in the late region of the SP2 mutant of simian virus 40 (SV40), a viable small-plaque variant isolated from a persistent infection of rhesus monkey kidney cells. The results indicate that six base pairs are deleted from that part of the SV40 genome in which the coding regions for the three virion proteins, VP1, VP2 and VP3, overlap. This implies that all three virion proteins are affected by the deletion. This finding is discussed with respect to the viability of SP2.

Animals↗
PubMed1980

Mapping of the two overlapping genes for polypeptides NS1 and NS2 on RNA segment 8 of influenza virus genome.

RNA segment 8 of the influenza virus genome is unique in coding for two polypeptides, NS1 (Mr, approximately 25,000) and NS2 (Mr, approximately 11,000). These polypeptides are synthesized from separate mRNA species. By using cloned DNA derived from RNA segment 8 (NS DNA) the two mRNAs have been mapped on segment 8 by hybridization of mRNAs with restriction endonuclease fragments of the DNA and nuclease S1 digestion methods. These data indicate that the body of the NS1 mRNA (approximately 850 nucleotides) maps at 0.05-0.95 units of the cloned NS DNA and the body of the NS2 mRNA (approximately 340 nucleotides) maps at 0.59-0.95 unitssuggesting that the two mRNAs are 3' coterminal and share the same poly(A) addition site. These positions of the mRNAs on the viral genome segment were confirmed in hybrid-arrested translation experiments using fragments of the cloned NS DNA to inhibit the synthesis in vitro of NS1 or NS2 polypeptides. In addition, in these translation experiments the use of certain DNA fragments resulted in premature termination of the NS1 polypeptide. From these data, it could be estimated that the termination of translation of NS1 is at approximately 0.76 map unit. Thus, the coding regions of the two mRNAs overlap by approximately 144-159 nucleotides, the equivalent of approximately 48-53 amino acids. Peptide mapping experiments indicated that polypeptides NS1 and NS2 do not share methionine- or leucine-containing tryptic peptides. The results obtained indicate the translation of the NS2 mRNA occurs in a reading frame different from that used for NS1.

Biological Transport, Active↗
PubMed1997

Role of gene overlap in the regulation of mRNA translation for mitochondrial cytochrome P-450c27/25 in the rat.

Previously published results have revealed sequence complementarity between the 5'-terminal regions of mRNAs for hepatic mitochondrial cytochrome P-450c27/ 25 (c27/25) and serine protease inhibitors (SPI) and predicted a role for this sequence overlap in both the regulation of c27/25 mRNA transcription and translation. The possibility that c27/25 mRNA forms an RNA duplex with complementary sequences of SPI mRNAs in vivo was demonstrated in the rat liver and COS-1 cells cotransfected with c27/25 and SPI2.1 plasmids. Quantitative evaluation of RNA duplex in COS-1 cells revealed that most of the c27/25 mRNA exists in duplex form when SPI2.1 mRNA was present at 5-10-fold that of c27/25 mRNA, a ratio comparable to that observed between these two RNAs in the liver. In cotransfected COS-1 cells with the same ratio of mRNAs, highly significant inhibition of the c27/25 mRNA translation (66-75%) was observed, while its transcription remained unaffected. The partial inhibition of c27/25 mRNA translation, even when most of it exists in duplex form, suggests that RNA duplex is undergoing some type of cytoplasmic processing to disengage c27/25 mRNA and make it available for translation. These results imply that abundant endogenous SPI RNAs are able to regulate the c27/25 gene expression.

Animals↗