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Results for “regulatory element transcripts”

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PubMed2006

Functionality of intergenic transcription: an evolutionary comparison.

Although a large proportion of human transcription occurs outside the boundaries of known genes, the functional significance of this transcription remains unknown. We have compared the expression patterns of known genes as well as intergenic transcripts within the ENCODE regions between humans and chimpanzees in brain, heart, testis, and lymphoblastoid cell lines. We find that intergenic transcripts show patterns of tissue-specific conservation of their expression, which are comparable to exonic transcripts of known genes. This suggests that intergenic transcripts are subject to functional constraints that restrict their rate of evolutionary change as well as putative positive selection to an extent comparable to that of classical protein-coding genes. In brain and testis, we find that part of this intergenic transcription is caused by widespread use of alternative promoters. Further, we find that about half of the expression differences between humans and chimpanzees are due to intergenic transcripts.

Animals↗

PubMed2007

hDREF regulates cell proliferation and expression of ribosomal protein genes.

Although ribosomal proteins (RPs) are essential cellular constituents in all living organisms, mechanisms underlying regulation of their gene expression in mammals remain unclear. We have established that 22 out of 79 human RP genes contain sequences similar to the human DREF (DNA replication-related element-binding factor; hDREF) binding sequence (hDRE) within 200-bp regions upstream of their transcriptional start sites. Electrophoretic gel mobility shift assays and chromatin immunoprecipitation analysis indicated that hDREF binds to hDRE-like sequences in the RP genes both in vitro and in vivo. In addition, transient luciferase assays revealed that hDRE-like sequences act as positive elements for RP gene transcription and cotransfection of an hDREF-expressing plasmid was found to stimulate RP gene promoter activity. Like that of hDREF, expression of RP genes is increased during the late G(1) to S phases, and depletion of hDREF using short hairpin RNA-mediated knockdown decreased RP gene expression and cell proliferation in normal human fibroblasts. Knockdown of the RPS6 gene also resulted in impairment of cell proliferation. These data suggest that hDREF is an important transcription factor for cell proliferation which plays roles in cell cycle-dependent regulation of a number of RP genes.

Base Sequence↗

PubMed2006

Different plant hormones regulate similar processes through largely nonoverlapping transcriptional responses.

Small-molecule hormones govern every aspect of the biology of plants. Many processes, such as growth, are regulated in similar ways by multiple hormones, and recent studies have revealed extensive crosstalk among different hormonal signaling pathways. These results have led to the proposal that a common set of signaling components may integrate inputs from multiple hormones to regulate growth. In this study, we tested this proposal by asking whether different hormones converge on a common set of transcriptional targets in Arabidopsis seedlings. Using publicly available microarray data, we analyzed the transcriptional effects of seven hormones, including abscisic acid, gibberellin, auxin, ethylene, cytokinin, brassinosteroid, and jasmonate. A high-sensitivity analysis revealed a surprisingly low number of common target genes. Instead, different hormones appear to regulate distinct members of protein families. We conclude that there is not a core transcriptional growth-regulatory module in young Arabidopsis seedlings.

Abscisic Acid↗

PubMed2006

Exploring transcriptional regulatory networks in the worm.

Using a yeast one-hybrid assay, Deplancke et al. (2006) report in this issue a protein-DNA interaction network for 72 gene promoters and 117 regulatory proteins expressed in cells of the nematode digestive tract. This study is a first step toward mapping transcriptional regulatory networks in distinct metazoan cell lineages and organs using a "gene-centered" approach.

Animals↗

PubMed2006

Predicting cis-acting elements of Lactobacillus plantarum by comparative genomics with different taxonomic subgroups.

Cis-acting elements in Lactobacillus plantarum were predicted by comparative analysis of the upstream regions of conserved genes and predicted transcriptional units (TUs) in different bacterial genomes. TUs were predicted for two species sets, with different evolutionary distances to L.plantarum. TUs were designated 'cluster of orthologous transcriptional units' (COT) when >50% of the genes were orthologous in different species. Conserved DNA sequences were detected in the upstream regions of different COTs. Subsequently, conserved motifs were used to scan upstream regions of all TUs. This method revealed 18 regulatory motifs only present in lactic acid bacteria (LAB). The 18 LAB-specific candidate regulatory motifs included 13 that were not described previously. These LAB-specific different motifs were found in front of genes encoding functions varying from cold shock proteins to RNA and DNA polymerases, and many unknown functions. The best-described LAB-specific motif found was the CopR-binding site, regulating expression of copper transport ATPases. Finally, all detected motifs were used to predict co-regulated TUs (regulons) for L.plantarum, and transcriptome profiling data were analyzed to provide regulon prediction validation. It is demonstrated that phylogenetic footprinting using different species sets can identify and distinguish between general regulatory motifs and LAB-specific regulatory motifs.

Base Sequence↗

PubMed2005

The Caenorhabditis elegans heterochronic regulator LIN-14 is a novel transcription factor that controls the developmental timing of transcription from the insulin/insulin-like growth factor gene ins-33 by direct DNA binding.

A temporal gradient of the novel nuclear protein LIN-14 specifies the timing and sequence of stage-specific developmental events in Caenorhabditis elegans. The profound effects of lin-14 mutations on worm development suggest that LIN-14 directly or indirectly regulates stage-specific gene expression. We show that LIN-14 can associate with chromatin in vivo and has in vitro DNA binding activity. A bacterially expressed C-terminal domain of LIN-14 was used to select DNA sequences that contain a putative consensus binding site from a pool of randomized double-stranded oligonucleotides. To identify candidates for genes directly regulated by lin-14, we employed DNA microarray hybridization to compare the mRNA abundance of C. elegans genes in wild-type animals to that in mutants with reduced or elevated lin-14 activity. Five of the candidate LIN-14 target genes identified by microarrays, including the insulin/insulin-like growth factor family gene ins-33, contain putative LIN-14 consensus sites in their upstream DNA sequences. Genetic analysis indicates that the developmental regulation of ins-33 mRNA involves the stage-specific repression of ins-33 transcription by LIN-14 via sequence-specific DNA binding. These results reinforce the conclusion that lin-14 encodes a novel class of transcription factor.

Animals↗

PubMed2006

Fluorescent protein expression driven by her4 regulatory elements reveals the spatiotemporal pattern of Notch signaling in the nervous system of zebrafish embryos.

Notch activation inhibits neuronal differentiation during development of the nervous system; however, the dynamic role of Notch signaling in individual cell lineages remains poorly understood. We have characterized 3.4 kb 5'-regulatory sequence of a Notch target gene, her4, and used it to drive fluorescent gene expression in transgenic lines where the spatiotemporal pattern of Notch activation can be examined in vivo. The 3.4 kb her4 promoter contains five predicted Su(H) binding sites of which two proximal sites were confirmed to be required for Notch-mediated transcriptional activation. Without Notch, Su(H) effectively represses transcription regulated by the promoter. Analyses of transgenic zebrafish showed that while the expression of proneural genes and Notch activation were both critical for endogenous her4 expression, reporter gene expression was primarily regulated by Notch activity. This study also showed that her4 may be differently regulated in sensory cranial ganglia, where Notch activity is not essential for her4 expression and where Su(H) may repress her4 expression. The establishment of a reporter line with Notch-Su(H)-dependent fluorescent gene expression provides a tool to explore the complex role of Notch signaling in the development of vertebrate nervous system.

Animals↗

PubMed2005

Promoter cloning and characterisation of the transcriptional regulation of the human thyrostimulin A2 subunit.

The novel heterodimeric glycoprotein hormone thyrostimulin consists of two unique subunits, A2 and B5. To understand its yet unknown transcriptional regulation, we characterised the 3.1-kb immediate 5'-flanking region of the human A2 gene localised on chromosome 11q13. In transient transfection assays this sequence exhibited promoter activity, which could be confined to nucleotides -506 to -347 relative to the ATG start codon. Interestingly, this minimal promoter appeared to be non-tissue-specific. Deletional, mutational and gel shift analyses revealed regulatory elements that are essential for the regulation of the A2 gene expression. Another noteworthy feature of this gene is the presence of silencer elements upstream and downstream of the promoter. To surmise, our results provide an initial step toward a detailed analysis of the underlying molecular mechanisms of the human thyrostimulin gene expression.

Animals↗

PubMed2004

Charting gene regulatory networks: strategies, challenges and perspectives.

One of the foremost challenges in the post-genomic era will be to chart the gene regulatory networks of cells, including aspects such as genome annotation, identification of cis-regulatory elements and transcription factors, information on protein-DNA and protein-protein interactions, and data mining and integration. Some of these broad sets of data have already been assembled for building networks of gene regulation. Even though these datasets are still far from comprehensive, and the approach faces many important and difficult challenges, some strategies have begun to make connections between disparate regulatory events and to foster new hypotheses. In this article we review several different genomics and proteomics technologies, and present bioinformatics methods for exploring these data in order to make novel discoveries.

Animals↗

PubMed1994

The UAS of the yeast GAPDH promoter consists of multiple general functional elements including RAP1 and GRF2 binding sites.

The upstream activating sequence (UAS) of TDH3, one of three genes encoding glyceraldehyde phosphate dehydrogenase in Saccharomyces cerevisiae, was characterized by using a series of external and internal deletion mutants of the TDH3 upstream region. The levels of activation by these deletions of transcription mediated through either the segment of TDH3 promoter or the segment of ADH1 (alcohol dehydrogenase 1 gene) promoter were quantitatively examined and the region between -583 and -447 was found to be required for full transcriptional activation with either promoter segment. It has been demonstrated that the protein binding site involved in the formation of two DNA-protein complexes is identical with the consensus RAP1 binding sequence by methylation interference assay. Surprisingly, the UAS fragment composed of the 22-mer sequence containing exclusively a RAP1 binding sequence showed full activation, suggesting that the RAP1-dependent transcriptional activation is a primary positive control in the TDH3 gene expression. In addition, a pair of inverted repeat sequences homologous to the binding sequence for GRF2, another yeast trans-acting factor, and directly repeated sequences containing a CATCC motif were also found upstream and downstream, respectively, of the RAP1 binding site. Deletion analysis suggested that these elements could also function as regulatory elements for transcription.

Base Sequence↗

PubMed2006

Negative regulation of defence and stress genes by EAR-motif-containing repressors.

Although positive control or activation mechanism(s) involved in plant defence- and stress-related gene expression is relatively well studied, little is known about what keeps defensive armoury under control when not needed. Recent reports suggest that transcriptional repression of gene expression by EAR-motif-containing repressor proteins plays a key role in modulating plant defence and stress responses.

Dehydration↗

PubMed2006

A mammalian promoter model links cis elements to genetic networks.

An accurate identification of gene promoters remains an important challenge. Computational approaches for this problem rely on promoter sequence attributes that are believed to be critical for transcription initiation. Here we report a probabilistic model that captures two important properties of promoters, not used by previous methods, viz., the location preference and co-occurrence of promoter elements. Additionally, we found that many of the position-specific DNA elements are strongly linked with the function of the gene product. For instance, a highly conserved motif CCTTT at -1 position is strongly associated with protein synthesis, cellular and tissue development. Our comparative analysis of promoter classes reveals that the promoters devoid of CpG islands are more conserved and have fewer alternative transcription start sites. The discovered links between promoter elements and gene function allows us to infer genetic networks from promoter elements. The web server for the PSPA promoter predictor is available at /PSPA.

Animals↗

PubMed2006

Hybrid transcription-mediated transgene regulation in plastids.

Plastids are semi-autonomous plant organelles with their own transcription and translation machinery that are suitable for producing high levels of transgenic proteins with a bona fide structure. However, the transcription of endogenous plastid genes is largely dependent on nuclear-encoded transcription factors, and the identification of these factors has implications for transgene regulation. A novel transcription system has recently been reported that works independently of the plastid transcription machinery and is potentially useful for transgene containment and to express genes with the assurance of high-level protein accumulation.

Gene Expression Regulation, Plant↗

PubMed2006

Inferring transcriptional modules from ChIP-chip, motif and microarray data.

'ReMoDiscovery' is an intuitive algorithm to correlate regulatory programs with regulators and corresponding motifs to a set of co-expressed genes. It exploits in a concurrent way three independent data sources: ChIP-chip data, motif information and gene expression profiles. When compared to published module discovery algorithms, ReMoDiscovery is fast and easily tunable. We evaluated our method on yeast data, where it was shown to generate biologically meaningful findings and allowed the prediction of potential novel roles of transcriptional regulators.

Algorithms↗

PubMed2005

BLADE-ON-PETIOLE-dependent signaling controls leaf and floral patterning in Arabidopsis.

NONEXPRESSOR OF PR GENES1 (NPR1) is a key regulator of the plant defense response known as systemic acquired resistance. Accumulation of the signal molecule salicylic acid (SA) leads to a change in intracellular redox potential, enabling NPR1 to enter the nucleus and interact with TGACG sequence-specific binding protein (TGA) transcription factors, which in turn bind to SA-responsive elements in the promoters of defense genes. Here, we show that two NPR1-like genes, BLADE-ON-PETIOLE1 (BOP1) and BOP2, function redundantly to control growth asymmetry, an important aspect of patterning in leaves and flowers. Phenotypes in the double mutant include leafy petioles, loss of floral organ abscission, and asymmetric flowers subtended by a bract. We demonstrate that BOP2 is localized to both the nucleus and the cytoplasm, but unlike NPR1, it is highly expressed in young floral meristems and in yeast interacts preferentially with the TGA transcription factor encoded by PERIANTHIA (PAN). In support of a biological relevance for this interaction, we show that bop1 bop2 and pan mutants share a pentamerous arrangement of first whorl floral organs, a patterning defect that is retained in bop1 bop2 pan triple mutants. Our data provide evidence that BOP proteins control patterning via direct interactions with TGA transcription factors and demonstrate that a signaling mechanism similar to that formally associated with plant defense is likely used for the control of developmental patterning.

Arabidopsis↗

PubMed2026

Identifying transcription factors controlling the basal expression of human MRP4 highlights a substantial role for Sp1.

The multidrug resistance protein 4 (MRP4/ABCC4) is a versatile efflux pump, known to transport several drugs but also signaling molecules such as cyclic nucleotides and lipid mediators. Based on this substrate spectrum and its broad tissue distribution, MRP4 plays a significant physiological and pathophysiological role in both the cardiovascular and oncological fields. However, the determinants of its gene expression are still incompletely defined. This study aimed to identify key regulatory elements and transcription factors that are essential for basal MRP4 expression. Using luciferase reporter assays with a series of 5'-deletion constructs, we identified a region upstream of the transcription start site as crucial for basal expression across diverse cell types. This region is evolutionary highly conserved and contains putative binding sites for Sp1 and Ets transcription factors. Site-directed mutagenesis of both binding elements resulted in a significant decrease in the promoter activity in HeLa and megakaryoblastic M07e cells. The binding of Sp1 to this region was further confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Finally, siRNA knockdown of Sp1 led to a significant decrease in MRP4 protein levels and function. In summary, we show that Sp1 binds to the MRP4 promoter and plays an essential role in the basal expression of MRP4, with Ets factors also potentially cooperating in this regulation.

Humans↗

PubMed2006

cis-Acting site controlling bidirectional transcription at the growth-differentiation transition in Dictyostelium discoideum.

A pair of adjacent genes, impA and dia1, are divergently transcribed but expressed at different stages in the life cycle of Dictyostelium discoideum. The intervening 654-bp region carries cis-acting regions that are essential for transcription in both directions as well as repression of dia1 in growing cells. We have focused on a 112-bp region proximal to dia1 that is essential for bidirectional transcription. Analyses of a set of internal deletions showed that the sequence between positions 80 and 97 (TTTGAATTTTTTGAATTT) is critical and that bases outside this region are dispensable. Site-directed mutations within this critical region confirmed the importance of this sequence for transcription both to the right and to the left. However, insertions of either 6 or 24 Ts into the run of 6 Ts separating the repeated GAA sequence had little effect on the functioning of the site in either direction, suggesting that factors recognize the half-sites TTGAATT separately. Inversion of the bases between positions 80 and 97 greatly reduced expression in both directions, indicating that orientation is critical for expression of both the nearby impA gene and the distal dia1 gene, which is more than 500 bp away. Comparison of 38 mutant constructs with multiple random variations in the region indicated that transcription factors may bind to a range of related sequences and still retain function. All functional constructs directed transcription both leftward and rightward, while all nonfunctional constructs were impaired for transcription in both directions. It appears that the same transcription complex controls transcription of both impA and dia1.

Animals↗

PubMed2005

Tcf- and Vent-binding sites regulate neural-specific geminin expression in the gastrula embryo.

Vertebrate neural development has been extensively investigated. However, it is unknown for any vertebrate gene how the onset of neural-specific expression in early gastrula embryos is transcriptionally regulated. geminin expression is among the earliest markers of dorsal, prospective neurectoderm at early gastrulation in Xenopus laevis. Here, we identified two 5' sequence domains that are necessary and sufficient to drive neural-specific expression during gastrulation in transgenic Xenopus embryos. Each domain contained putative binding sites for the transcription factor Tcf, which can mediate Wnt signaling and for Vent homeodomain proteins, transcriptional repressors that mediate BMP signaling. Results from embryos transgenic for constructs with mutated Tcf or Vent sites demonstrated that signaling through the Tcf sites was required for dorsal-specific expression at early gastrulation, while signaling through the Vent sites restricted geminin expression to the prospective neurectoderm at mid-gastrulation. Consistent with these results, geminin 5' regulatory sequences and endogenous Xgem responded positively to Wnt signaling and negatively to BMP signaling. The two 5' sequence domains were also conserved among geminin orthologs. Together, these results demonstrate that signaling through Tcf and Vent binding sites regulates transcription of geminin in prospective neurectoderm during gastrulation.

Animals↗