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PubMed2005

Promoter features related to tissue specificity as measured by Shannon entropy.

BACKGROUND: The regulatory mechanisms underlying tissue specificity are a crucial part of the development and maintenance of multicellular organisms. A genome-wide analysis of promoters in the context of gene-expression patterns in tissue surveys provides a means of identifying the general principles for these mechanisms. RESULTS: We introduce a definition of tissue specificity based on Shannon entropy to rank human genes according to their overall tissue specificity and by their specificity to particular tissues. We apply our definition to microarray-based and expressed sequence tag (EST)-based expression data for human genes and use similar data for mouse genes to validate our results. We show that most genes show statistically significant tissue-dependent variations in expression level. We find that the most tissue-specific genes typically have a TATA box, no CpG island, and often code for extracellular proteins. As expected, CpG islands are found in most of the least tissue-specific genes, which often code for proteins located in the nucleus or mitochondrion. The class of genes with no CpG island or TATA box are the most common mid-specificity genes and commonly code for proteins located in a membrane. Sp1 was found to be a weak indicator of less-specific expression. YY1 binding sites, either as initiators or as downstream sites, were strongly associated with the least-specific genes. CONCLUSIONS: We have begun to understand the components of promoters that distinguish tissue-specific from ubiquitous genes, to identify associations that can predict the broad class of gene expression from sequence data alone.

Animals↗
PubMed1998

A single-stranded DNA binding site in the human A1 adenosine receptor gene promoter.

Human A1 adenosine receptor gene expression is controlled by two independent promoters. The upstream promoter, promoter A, is subject to tissue specific regulation because not all cells express the mRNA associated with this promoter. One potential regulatory sequence located downstream of the TATA box is an AGG element appearing in a tandem repeat. In a previous study, transient transfection assays showed that mutations made in those AGG elements substantially reduced promoter activity. In the current study, DNase I footprinting indicated nuclear protein binding to this sequence between the TATA box and transcriptional start site. Electrophoretic mobility shift assay confirmed further the presence of an AGG element binding protein (AGBP) in human brain nuclear protein extracts. This binding protein has much higher affinity for single-stranded than for double-stranded DNA, and the binding is sequence specific. A series of assays also showed that AGBP is not related to the nuclear factor SP1 and the binding does not require metal cofactors. Therefore, AGBP is likely to be a specific single-stranded DNA binding protein that is required for the full expression of A1 adenosine receptor gene and particularly abundant in brain tissue.

Base Sequence↗
PubMed2000

Inferring regulatory elements from a whole genome. An analysis of Helicobacter pylori sigma(80) family of promoter signals.

Helicobacter pylori is adapted to life in a unique niche, the gastric epithelium of primates. Its promoters may therefore be different from those of other bacteria. Here, we determine motifs possibly involved in the recognition of such promoter sequences by the RNA polymerase using a new motif identification method. An important feature of this method is that the motifs are sought with the least possible assumptions about what they may look like. The method starts by considering the whole genome of H. pylori and attempts to infer directly from it a description for a family of promoters. Thus, this approach differs from searching for such promoters with a previously established description. The two algorithms are based on the idea of inferring motifs by flexibly comparing words in the sequences with an external object, instead of between themselves. The first algorithm infers single motifs, the second a combination of two motifs separated from one another by strictly defined, sterically constrained distances. Besides independently finding motifs known to be present in other bacteria, such as the Shine-Dalgarno sequence and the TATA-box, this approach suggests the existence in H. pylori of a new, combined motif, TTAAGC, followed optimally 21 bp downstream by TATAAT. Between these two motifs, there is in some cases another, TTTTAA or, less frequently, a repetition of TTAAGC separated optimally from the TATA-box by 12 bp. The combined motif TTAAGCx(21+/-2)TATAAT is present with no errors immediately upstream from the only two copies of the ribosomal 23 S-5 S RNA genes in H. pylori, and with one error upstream from the only two copies of the ribosomal 16 S RNA genes. The operons of both ribosomal RNA molecules are strongly expressed, representing an encouraging sign of the pertinence of the motifs found by the algorithms. In 25 cases out of a possible 30, the combined motif is found with no more than three substitutions immediately upstream from ribosomal proteins, or operons containing a ribosomal protein. This is roughly the same frequency of occurrence as for TTGACAx(15-19)TATAAT (with the same maximum number of substitutions allowed) described as being the sigma(70 )promoter sequence consensus in Bacillus subtilis and Escherichia coli. The frequency of occurrence of the new motif obtained, TTAAGCx(19-23)TATAAT, remains high when all protein genes in H. pylori are considered, as is the case for the TTGACAx(15-19)TATAAT motif in B. subtilis but not in E. coli.

Algorithms↗
PubMed1997

CRE-like response element regulates expression of rat alpha 2D-adrenergic receptor gene in vascular smooth muscle.

Contractile and binding studies indicate that alpha 2-adrenergic receptors (ARs) are differentially expressed by vascular smooth muscle cells (SMCs) according to vascular segment (artery, arteriole, vein). In the present study, alpha 2D-AR mRNA was two- to threefold higher in vena cava than in aorta. To understand vascular regulation of alpha 2D-AR expression in these cells, we sequenced 2.8 kb of the 5' flanking region of the alpha 2D-AR gene. Notable features include two potential TATA boxes, an adenosine 3',5'-cyclic monophosphate response element (CRE)-like binding element, and an Sp1 element. Comparison of the rat and human genes revealed an overall homology of 74% over the 1.87-kb sequence 5' to the translation initiator methionine, including complete homology at the distal TATA, CRE-like, and Sp1 sites, alpha 2D-AR transcription starts from the guanine nucleotide 18 base pair downstream from the distal TATA box. Reporter gene constructs demonstrated strong alpha 2D-AR promoter activity, but with several differences in construct activity, in both rat aorta and vena cava SMCs. Analysis of an essential promoter fragment revealed two regions protected by aorta and vena cava SMC nuclear proteins. The core sequences of these protected regions are TGACGCTA and TATAA. The former CRE-like element conferred specific binding of both aorta and vena cava nuclear proteins. In addition, promoter activity was increased 300% by forskolin or 8-bromoadenosine 3',5'-cyclic monophosphate, indicating that the CRE-like element may regulate alpha 2D-AR expression in vascular tissue.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Herpes simplex virus type 1 ICP4 promotes transcription preinitiation complex formation by enhancing the binding of TFIID to DNA.

Infected-cell polypeptide 4 (ICP4) of herpes simplex virus type 1 (HSV-1) activates the expression of many HSV genes during infection. It functions along with the cellular general transcription factors to increase the transcription rates of genes. In this study, an HSV late promoter consisting of only a TATA box and an INR element was immobilized on a magnetic resin and incubated with nuclear extracts or purified TFIID in the presence and absence of ICP4. Analysis of the complexes formed on these promoters revealed that ICP4 increased the formation of transcription preinitiation complexes (PICs) in a TATA box-dependent manner, as determined by the presence of ICP4, TFIID, TFIIB, and polymerase II on the promoter. With both nuclear extract and purified TFIID, it was determined that ICP4 helped TFIID bind to the promoter and the TATA box. These observations differed from those for the activator Gal4-VP16. As previously observed by others, Gal4-VP16 also increased the formation of PICs without helping TFIID bind to the promoter, suggesting that ICP4 and VP16 differ in their mechanism of activation and that ICP4 functions to facilitate PIC formation at an earlier step in the formation of PICs. We also observed that the DNA binding activity of ICP4 was not sufficient to help TFIID bind to the promoter and that the region of ICP4 that was responsible for this activity is located between residues 30 and 274. Taken together these results demonstrate that a specific region of ICP4 helps TFIID bind to the TATA box and that this in turn facilitates the formation of transcription PICs.

DNA↗
PubMed2005

Tenebrio molitor antifreeze protein gene identification and regulation.

The yellow mealworm, Tenebrio molitor, is a freeze susceptible, stored product pest. Its winter survival is facilitated by the accumulation of antifreeze proteins (AFPs), encoded by a small gene family. We have now isolated 11 different AFP genomic clones from 3 genomic libraries. All the clones had a single coding sequence, with no evidence of intervening sequences. Three genomic clones were further characterized. All have putative TATA box sequences upstream of the coding regions and multiple potential poly(A) signal sequences downstream of the coding regions. A TmAFP regulatory region, B1037, conferred transcriptional activity when ligated to a luciferase reporter sequence and after transfection into an insect cell line. A 143 bp core promoter including a TATA box sequence was identified. Its promoter activity was increased 4.4 times by inserting an exotic 245 bp intron into the construct, similar to the enhancement of transgenic expression seen in several other systems. The addition of a duplication of the first 120 bp sequence from the 143 bp core promoter decreased promoter activity by half. Although putative hormonal response sequences were identified, none of the five hormones tested enhanced reporter activity. These studies on the mechanisms of AFP transcriptional control are important for the consideration of any transfer of freeze-resistance phenotypes to beneficial hosts.

Amino Acid Sequence↗
PubMed2001

Cis and trans elements regulating expression of the varicella zoster virus gI gene.

We have identified cis- and trans-acting elements involved in the VZV IE62 protein-activated expression of the varicella zoster virus (VZV) gene which encodes the viral gI glycoprotein. The cis-acting elements include a non-canonical TATA box and a novel 19 base pair sequence located just upstream of the TATA element designated the "activating upstream sequence" or AUS. The AUS is a movable element and its presence results in IE62 activation of a chimeric promoter consisting of the VZV gC TATA box and the gI AUS. We have also determined that the VZV ORF 29 protein modulates the regulatory activity of the IE62 protein at the gI promoter. In combination with the IE62 transactivator, it yields a 10 to 15-fold increase in expression over the levels seen with the IE62 protein alone in T lymphocytes. The upmodulatory activity requires the presence of a 40 base pair sequence, designated the 29RE, which maps between positions -220 and -180 in the gI promoter. In this paper we review these and earlier findings from our laboratories concerning the regulation of the gI promoter.

Cell Line↗
PubMed2004

Transcriptional activation of the murine Muc5ac mucin gene in epithelial cancer cells by TGF-beta/Smad4 signalling pathway is potentiated by Sp1.

The nucleotide sequence of the pMS1 clone was submitted to the GenBank Nucleotide Sequence Database under accession number AF288076. Changes in the expression of mucin genes in gastrointestinal cancers is thought to contribute to the development of the disease. In our laboratory we have shown previously that MUC5AC is aberrantly expressed in rectosigmoid villous adenomas. However, the regulatory mechanisms underlying that altered profile of expression is unknown. In order to study its regulation at the transcriptional level, we have isolated and characterized 5.5 kb of the 5'-flanking region of the mouse Muc5ac mucin gene. The promoter is flanked by a TATA box and a transcriptional start site is located 22 bp downstream of the TATA box. Analysis of the sequence showed a high density of binding sites for Smad4, an essential factor in the signalling cascade activated by TGF-beta (transforming growth factor-beta), and Sp1, an important factor in the regulation of MUC5AC. This led us to study Muc5ac regulation by TGF-beta. We show that exogenous addition of TGF-beta to the cells induces Muc5ac endogenous expression, promoter activity and Smad4 binding to the promoter. By co-transfection studies we show that Smad4 is essential for Muc5ac promoter activation and that it does not synergize with Smad2 or Smad3. By gel-retardation and co-transfection assays, we identified Sp1 and Sp3 as important regulators of Muc5ac expression and showed that Smad4 and Sp1 act in a co-operative manner to transactivate Muc5ac promoter activity. Altogether these results bring new insights into the molecular mechanisms of TGF-beta-mediated up-regulation of Muc5ac and enhance our understanding as to how Muc5ac is regulated in certain pathologies of the gastrointestinal tract.

5' Flanking Region↗
PubMed1987

Analysis of the gene and multiple messenger ribonucleic acids (mRNAs) encoding human gastrin-releasing peptide: alternate RNA splicing occurs in neural and endocrine tissue.

Gastrin-releasing peptide (GRP), the mammalian homolog of the amphibian peptide bombesin, is encoded in man by a single gene located on chromosome 18. Restriction enzyme and DNA sequence analyses establish that the gene is 10 kilobases in size with two introns of 4.8 and 3.9 kilobases. Exon 1 encodes the 5'-untranslated region, the signal peptide, and the first 23 amino acids of GRP. Exon 2 encodes the remaining three complete amino acids of GRP and the first 74 amino acids of the GRP carboxy-terminal extension peptide. Hence, intron 1 interrupts the coding region of the bioactive portion of GRP between the first and second nucleotides for Gly, the 24th amino acid of GRP. Exon 3 encodes the remainder of the GRP-extension peptide and the 3'-untranslated region. Two GC-rich, potential regulatory sequences and a sequence associated with regulation by cAMP lie between the CAAT and TATA boxes; the primary transcriptional start site is located 30 bases downstream from the TATA box. The second intron has an alternate donor site at its 5'-end and an alternate acceptor site at its 3'-end. S1 nuclease mapping demonstrates that differential RNA splicing using these sites results in the similar expression of three GRP mRNAs in GRP-containing neurons (in stomach and brain) as well as in GRP-containing neuroendocrine cells (fetal lung). In addition, the pattern of RNA splicing is similar between normal tissue and neoplastic tissue (small cell carcinoma of the lung and medullary carcinoma of the thyroid).

Base Sequence↗
PubMed1991

Human alpha 1 (XIII) collagen gene. Multiple forms of the gene transcripts are generated through complex alternative splicing of several short exons.

The structure of the gene for the human alpha 1(XIII) collagen chain (COL13A1) was determined from genomic clones spanning 140,000 base pairs (bp), including about 3,000 bp of the 5'-end-flanking region and 5,000 bp of the 3'-end-flanking region. The gene was shown to contain 39 exons. There were eight exons of 27 bp, five of 36 bp, four of 54 bp, three of 45 bp, and two of 42 bp. The rest of the exons coding for translated sequences had sizes varying between 24 and 153 bp. The genomic clones did not contain exons 3 and 4 whose sizes could, however, be estimated from cDNA clones. S1 nuclease mapping and primer extension analyzes indicated five closely spaced initiation sites of transcription. Sequencing of the 5'-end-flanking region did not reveal a typical TATA box but a four times repeated TATTTAT sequence that may serve as true TATA boxes. Two CCAAT boxes were found starting at positions-13 and -194, and furthermore, the promoter region contains two GC boxes. Previous studies on alpha 1 (XIII) collagen cDNA and genomic clones showed that the primary transcript undergoes complex alternative splicing generating at least four different forms of mRNAs. The present work demonstrated that sequences of seven exons are alternatively used. These exons contain sequences coding for pure collagenous regions, pure noncollagenous regions, and an exon coding for a junction of a collagenous and noncollagenous domain.

Amino Acid Sequence↗
PubMed1991

Structure and expression of rat S-100 beta subunit gene.

The gene structure for S-100 beta subunit has been elucidated. The gene spans about 8 kbp and consists of 3 exons and 2 introns. The transcription initiation site was determined by an S1 nuclease mapping. The promoter region contains TATA-box-like and CAAT-box-like sequences. To examine the activity of the promoter sequence, a transfection of pS100 beta-lacZ fused gene to the cultured cells was carried out. C6 glioma cells showed a positive expression of beta-galactosidase. Gene-deletion experiments suggested the functional importance of the DNA fragment (22 bp) containing TATA-box-like and CAAT-box-like sequences. A factor protein that binds to the 100 bp DNA fragment containing the promoter sequence was specifically detected in the rat brain nuclear extract.

Animals↗
PubMed1995

The bovine papillomavirus 1 E2 protein contains two activation domains: one that interacts with TBP and another that functions after TBP binding.

The E2 transactivator of bovine papillomavirus type-1 is unable to activate minimal promoters in vivo that contain only E2 binding sites and a TATA box. This block can be overcome by over-expression of human TATA binding protein (TBP) or by the addition of either SP1 binding sites or an initiator element to the promoter, suggesting that the binding of TFIID may normally be a rate-limiting step for activation by E2. Surprisingly, purified E2 and TBP bind co-operatively to DNA in vitro when the sites are closely spaced. E2 does not affect the on rate of association but reduces the off rate. The E2 region responsible for this effect is located in the hinge region that links the classic transactivation and DNA binding domains. We demonstrate that the TBP stabilizing domain contributes in vivo to co-operativity with co-expressed TBP and to activation of the major late minimal promoter (MLP) containing E2 sites. In contrast, promoters with SP1 sites are activated to wild-type levels by such a mutant. This promoter specificity is also evident in vitro. A truncated E2 mutant, lacking the classic transactivation domain but containing the TBP stabilizing domain, stimulates transcription of the MLP in vitro, but does not activate promoters with SP1 sites. In conclusion, our results show that the E2 transactivation domain has a modular structure. We have identified one domain which probably acts at an early step in the assembly of the pre-initiation complex and which is involved in reducing the dissociation rate of bound TBP in vitro. The classic N-terminal activation domain of E2 might affect one or several step(s) in the assembly of the preinitiation complex occurring after the binding of TFIID.

Adenoviridae↗
PubMed1991

The functional BPV-1 E2 trans-activating protein can act as a repressor by preventing formation of the initiation complex.

The products encoded by the E2 open reading frame of the papillomaviruses are DNA-binding transcription factors involved in the positive or negative regulation of multiple viral promoters. To further understand the mechanisms by which the same transcription factor may act differentially, the full-length BPV-1 E2 protein was expressed and purified from yeast and assayed in vitro for its capacity to modulate transcription. E2 stimulated transcription of the HSV thymidine kinase (TK) promoter when E2-binding sites were positioned in an enhancer configuration approximately 100 bp upstream of the promoter start site. In contrast, the same full-length E2 protein repressed transcription of the HPV-18 E6/E7 P105 promoter. This repression was mediated through binding to the E2 DNA-binding site immediately upstream of the P105 promoter TATA box and could be abrogated by preincubation of the HPV-18 P105 promoter template with the nuclear extract allowing the formation of the preinitiation complex. In vitro DNA-binding experiments with purified E2 and TFIID showed that binding of E2 to its DNA target placed at different positions with respect to the TATA box differentially affects binding of TFIID to its cognate site. In these respects, E2 is similar to the bacteriophage lambda repressor, which can act either as a repressor or an activator of transcription depending on the position of its binding sites relative to the promoter sequences.

Animals↗
PubMed1995

Genomic cloning, characterization, and functional analysis of the major surface adhesin WI-1 on Blastomyces dermatitidis yeasts.

WI-1 is a 120-kDa surface protein adhesin on Blastomyces dermatitidis yeasts that binds CD18 and CD14 receptors on human macrophages. We isolated and analyzed a clone of genomic WI-1 to characterize this key adherence mechanism of the yeast. The 9.3-kilobase insert contains an open reading frame of 3438 nucleotides and no introns. The amino acid sequence of native WI-1 matches the deduced sequence of genomic WI-1 at positions 757-769, 901-913, and 1119-1138, demonstrating the cloned gene is authentic WI-1. The complete coding sequence has 30 highly conserved repeats of 24 amino acids arrayed in tandem in two noncontiguous regions of the protein. The repeat sequence is homologous to the Yersiniae adhesin invasin, the C terminus displays an epidermal growth factor-like domain, and the N terminus has a short hydrophobic sequence that may be a membrane-spanning domain. The tandem repeats are predicted to be at the exposed surface of the protein, thereby explaining the adhesive properties of WI-1. The WI-1 promoter contains a CAAT box (nucleotide positions 2287-2290), TATA box (2380-2385), and CT motif (2399-2508). Transcription is initiated within the CT motif at nucleotide 2431. A 5.5-kilobase subclone containing the full coding sequence of WI-1 was expressed as a histidine-tagged fusion protein in Escherichia coli. Recombinant WI-1 has the expected molecular mass of 120 kDa, is strongly recognized in Western blots by rabbit anti-WI-1 antiserum, and binds human macrophage receptors in the same manner as native WI-1. This work clarifies a key adherence mechanism of B. dermatitidis and will permit further analysis of WI-1-mediated attachment to host cells, receptors, and extracellular matrix.

Amino Acid Sequence↗
PubMed1997

Transcriptional repression by zinc finger peptides. Exploring the potential for applications in gene therapy.

A series of studies were performed to determine whether zinc finger peptides could efficiently repress transcription from RNA polymerase II promoters in vivo and to determine how such repression might depend on the position of the zinc finger binding site with respect to those of the TATA box or the initiator element. Promoter constructs were prepared with Zif268 binding sites inserted at various positions, and the activity of a reporter gene was measured in transfection studies. We found that the peptide containing the three zinc fingers of Zif268 could efficiently repress activated transcription when bound to a site near the TATA box (19-fold repression) or when bound to a site near the initiator element (18-fold repression). Repression was even more effective when the zinc finger peptide was bound to both of these sites (63-fold repression). Novel zinc finger peptides that had been selected via phage display also served as repressors of activated transcription, but repression with these proteins was somewhat less efficient than with the Zif268 peptide.

Amino Acid Sequence↗
PubMed1991

Strict distance requirement for transcriptional activation by two regulatory elements of the glucagon gene.

The glucagon gene is specifically expressed in A cells of the pancreatic islets. We have previously identified three functional DNA control elements within the 5'-flanking sequence of the glucagon gene: an upstream promoter element (G1), responsible for the A-cell-specific expression, and two enhancer-like elements (G2 and G3). Mutations within G1 completely abolished the enhancer activities of G2 and G3. We show here that the loss of transcriptional activity is not due to an absence of binding of nuclear proteins to G2 or G3, but rather to an essential role of G1 to enable G2 and G3 to exert their effects at a distance. When juxtaposed to the TATA box, both enhancers are capable of inducing transcription as efficiently as when an intact G1 is present. However, the tandem arrangement of G2 plus G3 does not result in additional transcriptional activity compared with a single element. We conclude that G2 and G3 are capable of directly activating transcription but in a highly distance-dependent fashion and without cooperatively interacting. G1 may thus serve only as a tissue-specific relay, bringing together factors that bind to enhancers and the TATA box.

Animals↗
PubMed1999

The structural basis for the oriented assembly of a TBP/TFB/promoter complex.

Recently the definition of the metazoan RNA polymerase II and archaeal core promoters has been expanded to include a region immediately upstream of the TATA box called the B recognition element (BRE), so named because eukaryal transcription factor TFIIB and its archaeal orthologue TFB interact with the element in a sequence-specific manner. Here we present the 2.4-A crystal structure of archaeal TBP and the C-terminal core of TFB (TFB(c)) in a complex with an extended TATA-box-containing promoter that provides a detailed picture of the stereospecific interactions between the BRE and a helix-turn-helix motif in the C-terminal cyclin repeat of TFB(c). This interaction is important in determining the level of basal transcription and explicitly defines the direction of transcription.

Amino Acid Sequence↗
PubMed1997

Mechanism of synergy between TATA and initiator: synergistic binding of TFIID following a putative TFIIA-induced isomerization.

The TFIID complex interacts with at least three types of core promoter elements within protein-coding genes, including TATA, initiator (Inr), and downstream promoter elements. We have begun to explore the mechanism by which the TFIID-Inr interaction leads to functional synergy between TATA and Inr elements during both basal and activated transcription. In DNase I footprinting assays, GAL4-VP16 recruited TFIID-TFIIA to core promoters containing either a TATA box, an Inr, or both TATA and Inr elements, with synergistic interactions apparent on the TATA-Inr promoter. Appropriate spacing between the two elements was essential for the synergistic binding. Despite the sequence-specific TFIID-Inr interactions, gel shift experiments revealed that TFIID alone possesses similar affinities for the TATA-Inr and TATA promoters. Interestingly, however, recombinant TFIIA strongly and selectively enhanced TFIID binding to the TATA-Inr promoter, with little effect on binding to the TATA promoter. Studies of the natural adenovirus major late promoter confirmed these findings, despite the existence of specific but nonfunctional TFIID interactions downstream of the Inr in that promoter. These results suggest that a TFIIA-induced conformational change is essential for the sequence-specific TFIID-Inr interaction to occur with sufficient affinity to support the functional synergism between TATA and Inr elements.

Animals↗