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Results for “regulatory module”

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At least 217 records · Page 12Linked to original sources

PubMed2006

Phosphoinositides and Rho proteins spatially regulate actin polymerization to initiate and maintain directed movement in a one-dimensional model of a motile cell.

Gradient sensing, polarization, and chemotaxis of motile cells involve the actin cytoskeleton, and regulatory modules, including the phosphoinositides (PIs), their kinases/phosphatases, and small GTPases (Rho proteins). Here we model their individual components (PIP1, PIP2, PIP3; PTEN, PI3K, PI5K; Cdc42, Rac, Rho; Arp2/3, and actin), their interconversions, interactions, and modular functions in the context of a one-dimensional dynamic model for protrusive cell motility, with parameter values derived from in vitro and in vivo studies. In response to a spatially graded stimulus, the model produces stable amplified internal profiles of regulatory components, and initiates persistent motility (consistent with experimental observations). By connecting the modules, we find that Rho GTPases work as a spatial switch, and that the PIs filter noise, and define the front versus back. Relatively fast PI diffusion also leads to selection of a unique pattern of Rho distribution from a collection of possible patterns. We use the model to explore the importance of specific hypothesized interactions, to explore mutant phenotypes, and to study the role of actin polymerization in the maintenance of the PI asymmetry. We also suggest a mechanism to explain the spatial exclusion of Cdc42 and PTEN and the inability of cells lacking active Cdc42 to properly detect chemoattractant gradients.

Actins↗

PubMed2001

HLA-G unique promoter region: functional implications.

In contrast to the highly polymorphic HLA class Ia genes that exhibit a broad somatic tissue distribution, the restricted constitutive expression of HLA-G to trophoblast and a subset of thymic epithelial cells suggests tight transcriptional control of this MHC class Ib gene. Transactivation of MHC class I genes is mediated by three major regulatory modules present in their promoter region namely enhancer A, ISRE, and SXY. The 220-bp promoter sequence of HLA-G comprises modified enhancer A and SXY modules and lacks the ISRE which renders this gene unresponsive to NK-kappaB, IRF1, and class II transactivator DNA-binding factors. A number of other HLA-G upstream regulatory elements have recently been described. Using different transgenic HLA-G mouse models under the control of the HLA-G promoter, several groups have shown by in situ hybridization and/or qualitative or quantitative RT-PCR that constitutive HLA-G transcriptional expression in placental tissue decreased with gestational time. This suggests that once the placenta is fully formed, the functions of HLA-G might not be so crucial.

Animals↗

PubMed2002

HLA-G transactivation by cAMP-response element-binding protein (CREB). An alternative transactivation pathway to the conserved major histocompatibility complex (MHC) class I regulatory routes.

The expression of HLA-G in extravillous cytotrophoblast cells coincides with a general lack of classical major histocompatibility complex (MHC) class I expression in this tissue. This differential expression of HLA-G and classical HLA class I molecules in trophoblasts suggests a tight transcriptional control of MHC class I genes. Transactivation of the classical MHC class I genes is mediated by two groups of juxtaposed cis-acting elements that can be viewed as regulatory modules. Both modules are divergent in HLA-G, rendering this gene unresponsive to NF-kappaB, IRF1, and class II transactivator (CIITA)-mediated induction pathways. In this study, we searched for alternative regulatory elements in the 1438-bp HLA-G promoter region. HLA-G was not responsive to interferon-alpha (IFNalpha), IFNbeta, or IFNgamma, despite the presence of an upstream ISRE binding IRF1 in vitro. However, the HLA-G promoter contains three CRE/TRE elements with binding affinity for CREB/ATF and Fos/Jun proteins both in vitro and in vivo. In transient transfection assays, it was shown that HLA-G transactivation is regulated by CREB, CREB-binding protein (CBP), and p300. Moreover, immunohistochemical analysis demonstrated that HLA-G is co-expressed with CREB and CBP in extravillous cytotrophoblasts, revealing the in vivo relevance of this transactivation pathway. This implies a unique regulation of HLA-G transcription among the MHC class I genes.

Chromatin↗

PubMed2003

The class III adenylyl cyclases: multi-purpose signalling modules.

cAMP serves as a second messenger in virtually all organisms. The most wide-spread class of cAMP-generating enzymes are the class III adenylyl cyclases. Most class III adenylyl cyclases are multi-domain proteins. The catalytic domains exclusively work as dimers, catalysis proceeds at the dimer interface, so that both monomers provide catalytic residues to each catalytic center. Inspection of amino acid sequence profiles suggests a division of the class III adenylyl cyclases in to four subclasses, class IIIa-IIId. Genome projects and postgenomic analysis have provided novel aspects in terms of catalysis and regulation. Alterations in the canonical catalytic residues occur in all four subclasses suggesting a plasticity of the catalytic mechanisms. The vast variety of additional, probably regulatory modules found in class III adenylyl cyclases obviously reflects a large collection of regulatory inputs the catalytic domains have adapted to. The large versatility of class III adenylyl cyclase catalytic domains remains a major scientific challenge.

Adenylyl Cyclases↗

PubMed2000

Distinct regulatory elements direct delta1 expression in the nervous system and paraxial mesoderm of transgenic mice.

The Delta1 gene encodes one of the Notch ligands in mice. Delta1 is expressed during early embryogenesis in a complex and dynamic pattern in the paraxial mesoderm and neuroectoderm, and is essential for normal somitogenesis and neuronal differentiation. Molecular components thought to act in response to ligand binding and Notch activation have been identified in different species. In contrast, little is known about the transcriptional regulation of Notch receptors and their ligands. As a first step to identify upstream factors regulating Delta1 expression in different tissues, we searched for cis-regulatory regions in the Delta1 promoter able to direct heterologous gene expression in a tissue specific manner in transgenic mice. Our results show that a 4.3 kb genomic DNA fragment of the Delta1 gene is sufficient in a lacZ reporter transgene to reproduce most aspects of Delta1 expression from the primitive streak stage to early organogenesis. Using a minimal Delta1 promoter we also show that this upstream region contains distinct regulatory modules that individually direct tissue-specific transgene expression in subdomains of the endogenous expression pattern. It appears that expression in the paraxial mesoderm depends on the interaction of multiple positive and negative regulatory elements. We also find that at least some regulatory sequences required for transgene expression in subdomains of the neural tube have been maintained during the evolution of mammals and teleost fish, suggesting that part of the regulatory network that controls expression of Delta genes may be conserved.

Animals↗

PubMed2003

Retinoic acid binds to the C2-domain of protein kinase C(alpha).

Protein kinase C(alpha) (PKC(alpha)) is a key enzyme regulating the physiology of cells and their growth, differentiation, and apoptosis. PKC activity is known to be modulated by all-trans retinoic acid (atRA), although neither the action mechanism nor even the possible binding to PKCs has been established. Crystals of the C2-domain of PKC(alpha), a regulatory module in the protein that binds Ca(2+) and acidic phospholipids, have now been obtained by cocrystallization with atRA. The crystal structure, refined at 2.0 A resolution, shows that RA binds to the C2-domain in two locations coincident with the two binding sites previously reported for acidic phospholipids. The first binding site corresponds to the Ca(2+)-binding pocket, where Ca(2+) ions mediate the interactions of atRA with the protein, as they do with acidic phospholipids. The second binding site corresponds to the conserved lysine-rich cluster localized in beta-strands three and four. These observations are strongly supported by [(3)H]-atRA-binding experiments combined with site-directed mutagenesis. Wild-type C2-domain binds 2 mol of atRA per mol of protein, while the rate reduces to one in the case of C2-domain variants, in which mutations affect either Ca(2+) coordination or the integrity of the lysine-rich cluster site. Competition between atRA and acidic phospholipids to bind to PKC is a possible mechanism for modulating PKC(alpha) activity.

Animals↗

PubMed2004

Clusters of regulatory signals for RNA polymerase II transcription associated with Alu family repeats and CpG islands in human promoters.

Primate genomes contain a very large number of short interspersed GC-rich repeats of the Alu family, which are abundant in introns and intergenic spacers but also present in 5' flanking regions of genes enriched in binding motifs (BMs) for transcription factors and frequently containing CpG islands. Here we studied whether CpG islands located in promoters of human genes overlap with Alu repeats and with clusters of BMs for the zinc-finger transcription factors Sp1, estrogen receptor alpha, and YY1. The presence of estrogen-response elements in Alu was shown earlier and here we confirm the presence in the consensus Alu sequence of the binding sites for Sp1 and YY1. Analyzing >5000 promoters from the two databases we found that Alu sequences are underrepresented in promoters compared to introns and that approximately 4% of CpG islands located within the -1000 to +200 segments of human promoters overlap with Alu repeats. Although this fraction was found to be lower for proximal segments of promoters (-500 to +100), our results indicate that a significant number (>1000) of all human genes may be controlled by Alu-associated CpG islands. Analysis of clustering of potential BMs for the indicated transcription factors within some promoters also suggests that the Alu family contributed to the evolution of transcription cis-regulatory modules in the human genome. It is important that among Alu sequences overlapping with CpG islands in promoters a large fraction of members of the old Alu subfamilies is found, suggesting extensive retroposon-assisted regulatory genome evolution during the divergence of the primates.

5' Flanking Region↗

PubMed2006

Electron transfer by neuronal nitric-oxide synthase is regulated by concerted interaction of calmodulin and two intrinsic regulatory elements.

The nitric-oxide synthases (NOSs) are modular, cofactor-containing enzymes, divided into a heme-containing oxygenase domain and an FMN- and FAD-containing reductase domain. The domains are connected by a calmodulin (CaM)-binding sequence, occupancy of which is required for nitric oxide (NO) production. Two additional CaM-modulated regulatory elements are present in the reductase domains of the constitutive isoforms, the autoregulatory region (AR) and the C-terminal tail region. Deletion of the AR reduces CaM stimulation of electron flow through the reductase domain from 10-fold in wild-type nNOS to 2-fold in the mutant. Deletion of the C terminus yields an enzyme with greatly enhanced reductase activity in the absence of CaM but with activity equivalent to that of wild-type enzyme in its presence. A mutant in which both the AR and C terminus were deleted completely loses CaM modulation through the reductase domain. Thus, transduction of the CaM effect through the reductase domain of nNOS is dependent on these elements. Formation of nitric oxide is, however, still stimulated by CaM in all three mutants. A CaM molecule in which the N-terminal lobe was replaced by the C-terminal lobe (CaM-CC) supported NO synthesis by the deletion mutants but not by wild-type nNOS. We propose a model in which the AR, the C-terminal tail, and CaM interact directly to regulate the conformational state of the reductase domain of nNOS.

Amino Acid Sequence↗

PubMed2026

Mapping the Immune cell-specific gene regulatory network in bipolar disorder: A framework from scTWMR to exploratory drug-target annotation.

BACKGROUND: Although the involvement of the immune system in the genetic susceptibility of bipolar disorder (BD) is widely acknowledged, the causal relationship between gene expression in specific immune cell subtypes and BD requires systematic elucidation. METHODS: We implemented an analytical framework integrating single-cell transcriptome-wide Mendelian randomization (scTWMR) with colocalization analysis. This approach utilized cis-expression quantitative trait loci (cis-eQTLs) derived from 14 distinct immune cell types as instrumental variables to interrogate BD genome-wide association study (GWAS) summary statistics (comprising 41,917 cases and 371,549 controls). Subsequent investigations encompassed functional enrichment analysis, protein-protein interaction (PPI) network construction, phenome-wide association study (PheWAS), and performed an exploratory drug-target annotation. RESULTS: Our analysis identified 33 gene-immune cell associations. Colocalization analysis provided robust evidence (PPH4 > 90%) for shared causal variants implicating the MAD1L1, APOM, and NFKBIL1 loci. Significantly enriched biological pathways included cell cycle regulation, circadian rhythm entrainment, and neuroinflammation. The PPI network revealed a core regulatory module centered on histone-encoding and immune-related genes. Exploratory drug-target annotation nominated compounds for further investigation for compounds targeting APOM, TMEM258, and NFKBIL1. CONCLUSION: This study systematically delineates a genetically supported regulatory network of immune cell-specific gene expression in BD, predominantly implicating CD8⁺ effector T cells, plasma cells, and B cells. The findings corroborate established pathological pathways while uncovering novel cell type-specific therapeutic targets, thereby providing a genetic framework for prioritizing candidate targets for future investigation.

Bipolar disorder↗

PubMed1992

Regulation of thyrotropin receptor gene expression in rat FRTL-5 thyroid cells.

TSH receptor mRNA levels in FRTL-5 thyroid cells are autoregulated at a transcriptional level by the same hormones required for the growth and function of the cells: TSH, insulin, and insulin-like growth factor-I (IGF-I). Thus, the ability of TSH, via its cAMP signal, to down-regulate steady state receptor mRNA levels is preceded by the action of TSH to decrease pre-mRNA levels in nuclear run-on assays to the same quantitative level as evident in Northern analyses. In contrast, the receptor mRNA half-life is shown not to change when down-regulation is reversed by withdrawing TSH in the presence or absence of actinomycin-D. Evidence is additionally provided that TSH receptor mRNA levels are increased by insulin, IGF-I, or calf serum in both Northern and run-on assays. This action cannot be duplicated by hydrocortisone and is evident at more than 20-fold lower concentrations of IGF-I than insulin. Moreover, insulin, IGF-I, and/or calf serum are required for the autoregulatory negative transcriptional regulation of the TSH receptor by TSH/cAMP, as is the case for thyroglobulin. This occurs despite the opposite actions of TSH/cAMP on the two genes, positive in the case of thyroglobulin and negative with TSH receptor. The positive and negative regulatory actions, respectively, of insulin/IGF-I and TSH on receptor gene expression are associated with coincident increases or decreases in cell surface receptors measured by [125I]TSH binding. The autoregulation additionally involves the interplay of a second cAMP-modulated regulatory factor, one which up-regulates TSH receptor mRNA levels rather than causing down-regulation. Thus, cycloheximide inhibits the transcriptional action of both TSH/cAMP and insulin/IGF-I/serum within 4 h, i.e. a rapidly synthesized protein is an intermediate in both cases. The presence of cycloheximide for as little as 1 h, however, uncovers the ability of TSH/cAMP to increase TSH receptor mRNA levels. This activity is the result of the action of a stable cAMP-induced activator which can be detected physiologically, i.e. in the absence of cycloheximide. For example, low levels of a cAMP analog (0.2 mM), as opposed to high levels (greater than 1 mM), can increase TSH receptor RNA levels. Low levels also accelerate the insulin/IGF-I-dependent return of receptor mRNA to normal levels after TSH withdrawal.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Genome-wide prediction of transcriptional regulatory elements of human promoters using gene expression and promoter analysis data.

BACKGROUND: A complete understanding of the regulatory mechanisms of gene expression is the next important issue of genomics. Many bioinformaticians have developed methods and algorithms for predicting transcriptional regulatory mechanisms from sequence, gene expression, and binding data. However, most of these studies involved the use of yeast which has much simpler regulatory networks than human and has many genome wide binding data and gene expression data under diverse conditions. Studies of genome wide transcriptional networks of human genomes currently lag behind those of yeast. RESULTS: We report herein a new method that combines gene expression data analysis with promoter analysis to infer transcriptional regulatory elements of human genes. The Z scores from the application of gene set analysis with gene sets of transcription factor binding sites (TFBSs) were successfully used to represent the activity of TFBSs in a given microarray data set. A significant correlation between the Z scores of gene sets of TFBSs and individual genes across multiple conditions permitted successful identification of many known human transcriptional regulatory elements of genes as well as the prediction of numerous putative TFBSs of many genes which will constitute a good starting point for further experiments. Using Z scores of gene sets of TFBSs produced better predictions than the use of mRNA levels of a transcription factor itself, suggesting that the Z scores of gene sets of TFBSs better represent diverse mechanisms for changing the activity of transcription factors in the cell. In addition, cis-regulatory modules, combinations of co-acting TFBSs, were readily identified by our analysis. CONCLUSION: By a strategic combination of gene set level analysis of gene expression data sets and promoter analysis, we were able to identify and predict many transcriptional regulatory elements of human genes. We conclude that this approach will aid in decoding some of the important transcriptional regulatory elements of human genes.

Algorithms↗

PubMed2005

Making very similar embryos with divergent genomes: conservation of regulatory mechanisms of Otx between the ascidians Halocynthia roretzi and Ciona intestinalis.

Ascidian embryos develop with a fixed cell lineage into simple tadpoles. Their lineage is almost perfectly conserved, even between the evolutionarily distant species Halocynthia roretzi and Ciona intestinalis, which show no detectable sequence conservation in the non-coding regions of studied orthologous genes. To address how a common developmental program can be maintained without detectable cis-regulatory sequence conservation, we compared in both species the regulation of Otx, a gene with a shared complex expression pattern. We found that in Halocynthia, the regulatory logic is based on the use of very simple cell line-specific regulatory modules, the activities of which are conserved, in most cases, in the Ciona embryo. The activity of each of these enhancer modules relies on the conservation of a few repeated crucial binding sites for transcriptional activators, without obvious constraints on their precise number, order or orientation, or on the surrounding sequences. We propose that a combination of simplicity and degeneracy allows the conservation of the regulatory logic, despite drastic sequence divergence. The regulation of Otx in the anterior endoderm by Lhx and Fox factors may even be conserved with vertebrates.

Animals↗

PubMed2004

Decoding human regulatory circuits.

Clusters of transcription factor binding sites (TFBSs) which direct gene expression constitute cis-regulatory modules (CRMs). We present a novel algorithm, based on Gibbs sampling, which locates, de novo, the cis features of these CRMs, their component TFBSs, and the properties of their spatial distribution. The algorithm finds 69% of experimentally reported TFBSs and 85% of the CRMs in a reference data set of regions upstream of genes differentially expressed in skeletal muscle cells. A discriminant procedure based on the output of the model specifically discriminated regulatory sequences in muscle-specific genes in an independent test set. Application of the method to the analysis of 2710 10-kb fragments upstream of annotated human genes identified 17 novel candidate modules with a false discovery rate </=0.05, demonstrating the applicability of the method to genome-scale data.

Algorithms↗

PubMed2004

Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA.

MHC class II (MHC-II) genes are regulated by an enhanceosome complex containing two gene-specific transcription factors, regulatory factor X complex (RFX) and CIITA. These factors assemble on a strictly conserved regulatory module (S-X-X2-Y) found immediately upstream of the promoters of all classical and nonclassical MHC-II genes as well as the invariant chain (Ii) gene. To identify new targets of RFX and CIITA, we developed a computational approach based on the unique and highly constrained architecture of the composite S-Y motif. We identified six novel S'-Y' modules situated far away from the promoters of known human RFX- and CIITA-controlled genes. Four are situated at strategic positions within the MHC-II locus, and two are found within the Ii gene. These S'-Y' modules function as transcriptional enhancers, are bona fide targets of RFX and CIITA in B cells and IFN-gamma-induced cells, and induce broad domains of histone hyperacetylation. These results reveal a hitherto unexpected level of complexity involving long distance control of MHC-II expression by multiple distal regulatory elements.

Acetylation↗

PubMed2005

Reliable prediction of transcription factor binding sites by phylogenetic verification.

We present a statistical methodology that largely improves the accuracy in computational predictions of transcription factor (TF) binding sites in eukaryote genomes. This method models the cross-species conservation of binding sites without relying on accurate sequence alignment. It can be coupled with any motif-finding algorithm that searches for overrepresented sequence motifs in individual species and can increase the accuracy of the coupled motif-finding algorithm. Because this method is capable of accurately detecting TF binding sites, it also enhances our ability to predict the cis-regulatory modules. We applied this method on the published chromatin immunoprecipitation (ChIP)-chip data in Saccharomyces cerevisiae and found that its sensitivity and specificity are 9% and 14% higher than those of two recent methods. We also recovered almost all of the previously verified TF binding sites and made predictions on the cis-regulatory elements that govern the tight regulation of ribosomal protein genes in 13 eukaryote species (2 plants, 4 yeasts, 2 worms, 2 insects, and 3 mammals). These results give insights to the transcriptional regulation in eukaryotic organisms.

Base Sequence↗

PubMed2004

Determination of local statistical significance of patterns in Markov sequences with application to promoter element identification.

High-level eukaryotic genomes present a particular challenge to the computational identification of transcription factor binding sites (TFBSs) because of their long noncoding regions and large numbers of repeat elements. This is evidenced by the noisy results generated by most current methods. In this paper, we present a p-value-based scoring scheme using probability generating functions to evaluate the statistical significance of potential TFBSs. Furthermore, we introduce the local genomic context into the model so that candidate sites are evaluated based both on their similarities to known binding sites and on their contrasts against their respective local genomic contexts. We demonstrate that our approach is advantageous in the prediction of myogenin and MEF2 binding sites in the human genome. We also apply LMM to large-scale human binding site sequences in situ and found that, compared to current popular methods, LMM analysis can reduce false positive errors by more than 50% without compromising sensitivity. This improvement will be of importance to any subsequent algorithm that aims to detect regulatory modules based on known PSSMs.

Algorithms↗

PubMed2003

Expression of Sox3 throughout the developing central nervous system is dependent on the combined action of discrete, evolutionarily conserved regulatory elements.

SOX3 is one of the earliest neural markers in vertebrates and is thought to play a role in specifying neuronal fate. To investigate the regulation of Sox3 expression we identified cis-regulatory regions in the Sox3 promoter that direct tissue-specific heterologous marker gene expression in transgenic mice. Our results show that an 8.3 kb fragment, comprising 3 kb upstream and 3 kb downstream of the Sox3 transcriptional unit, is sufficient in a lacZ reporter construct to reproduce most aspects of Sox3 expression during CNS development from headfold to midgestation stages. The apparently uniform expression of Sox3 in the neural tube depends, however, on the combined action of distinct regulatory modules within this 8.3 kb region. Each of these gives expression in a subdomain of the complete expression pattern. These are restricted along both the rostral-caudal and dorso-ventral axes and can be quite specific, one element giving expression largely confined to V2 interneuron precursors. We also find that at least some of the regulatory sequences are able to drive expression of the transgene in the CNS Xenopus laevis embryos in a manner that reflects the endogenous Sox3 expression pattern. These results imply that the underlying mechanism regulating early CNS patterning is conserved, despite several substantial differences in neurogenesis between mammals and amphibians.

Animals↗

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↗