Dataset Information

Transcription Factor Binding Site Enrichment Analysis in Co-Expression Modules in Celiac Disease.

ABSTRACT: The aim of this study was to construct celiac co-expression patterns at a whole genome level and to identify transcription factors (TFs) that could drive the gliadin-related changes in coordination of gene expression observed in celiac disease (CD). Differential co-expression modules were identified in the acute and chronic responses to gliadin using expression data from a previous microarray study in duodenal biopsies. Transcription factor binding site (TFBS) and Gene Ontology (GO) annotation enrichment analyses were performed in differentially co-expressed genes (DCGs) and selection of candidate regulators was performed. Expression of candidates was measured in clinical samples and the activation of the TFs was further characterized in C2BBe1 cells upon gliadin challenge. Enrichment analyses of the DCGs identified 10 TFs and five were selected for further investigation. Expression changes related to active CD were detected in four TFs, as well as in several of their in silico predicted targets. The activation of TFs was further characterized in C2BBe1 cells upon gliadin challenge, and an increase in nuclear translocation of CAMP Responsive Element Binding Protein 1 (CREB1) and IFN regulatory factor-1 (IRF1) in response to gliadin was observed. Using transcriptome-wide co-expression analyses we are able to propose novel genes involved in CD pathogenesis that respond upon gliadin stimulation, also in non-celiac models.

SUBMITTER: Romero-Garmendia I

PROVIDER: S-EPMC5977185 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Transcription Factor Binding Site Enrichment Analysis in Co-Expression Modules in Celiac Disease.

Romero-Garmendia Irati I Garcia-Etxebarria Koldo K Hernandez-Vargas Hector H Santin Izortze I Jauregi-Miguel Amaia A Plaza-Izurieta Leticia L Cros Marie-Pierre MP Legarda Maria M Irastorza Iñaki I Herceg Zdenko Z Fernandez-Jimenez Nora N Bilbao Jose Ramon JR

Genes 20180510 5

The aim of this study was to construct celiac co-expression patterns at a whole genome level and to identify transcription factors (TFs) that could drive the gliadin-related changes in coordination of gene expression observed in celiac disease (CD). Differential co-expression modules were identified in the acute and chronic responses to gliadin using expression data from a previous microarray study in duodenal biopsies. Transcription factor binding site (TFBS) and Gene Ontology (GO) annotation e ...[more]

PMID: 29748492

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Project description:BackgroundThe use of global gene expression profiling is a well established approach to understand biological processes. One of the major goals of these investigations is to identify sets of genes with similar expression patterns. Such gene signatures may be very informative and reveal new aspects of particular biological processes. A logical and systematic next step is to reduce the identified gene signatures to the regulatory components that induce the relevant gene expression changes. A central issue in this context is to identify transcription factors, or transcription factor binding sites (TFBS), likely to be of importance for the expression of the gene signatures.ResultsWe develop a strategy that efficiently produces TFBS/promoter databases based on user-defined criteria. The resulting databases constitute all genes in the Santa Cruz database and the positions for all TFBS provided by the user as position weight matrices. These databases are then used for two purposes, to identify significant TFBS in the promoters in sets of genes and to identify clusters of co-occurring TFBS. We use two criteria for significance, significantly enriched TFBS in terms of total number of binding sites for the promoters, and significantly present TFBS in terms of the fraction of promoters with binding sites. Significant TFBS are identified by a re-sampling procedure in which the query gene set is compared with typically 10(5) gene lists of similar size randomly drawn from the TFBS/promoter database. We apply this strategy to a large number of published ChIP-Chip data sets and show that the proposed approach faithfully reproduces ChIP-Chip results. The strategy also identifies relevant TFBS when analyzing gene signatures obtained from the MSigDB database. In addition, we show that several TFBS are highly correlated and that co-occurring TFBS define functionally related sets of genes.ConclusionsThe presented approach of promoter analysis faithfully reproduces the results from several ChIP-Chip and MigDB derived gene sets and hence may prove to be an important method in the analysis of gene signatures obtained through ChIP-Chip or global gene expression experiments. We show that TFBS are organized in clusters of co-occurring TFBS that together define highly coherent sets of genes.

Project description:Empirical studies have revealed that regulatory DNA sequences such as enhancers or promoters often harbor multiple binding sites for the same transcription factor. Such "homotypic site clustering" has been hypothesized as arising out of functional requirements of the sequences. Here, we propose an alternative explanation of this phenomenon that multisite enhancers are common because they are favored by evolutionary sampling of the genotype-phenotype landscape. To test this hypothesis, we developed a new computational framework specialized for population genetic simulations of enhancer evolution. It uses a thermodynamics-based model of enhancer function, integrating information from strong as well as weak binding sites, to determine the strength of selection. Using this framework, we found that even when simpler genotypes exist for a desired strength of regulation, relatively complex genotypes (enhancers with more sites) are more readily reached by the simulated evolutionary process. We show that there are more ways to "build" a fit genotype with many weak sites than with a few strong sites, and this is why evolution finds complex genotypes more often. Our claims are consistent with an empirical analysis of binding site content in enhancers characterized in Drosophila melanogaster and their orthologs in other Drosophila species. We also characterized a subtle but significant difference between genotypes likely to be sampled by evolution and equally fit genotypes one would obtain by uniform sampling of the fitness landscape, that is, an "evolutionary signature" in enhancer sequences. Finally, we investigated potential effects of other factors, such as rugged fitness landscapes, short local duplications, and noise characteristics of enhancers, on the emergence of homotypic site clustering. Homotypic site clustering is an important contributor to the complexity and function of cis-regulatory sequences. This work provides a simple null hypothesis for its origin, against which alternative adaptationist explanations may be evaluated, and cautions against "evolutionary mirages" present in common features of genomic sequence. The quantitative framework we develop here can be used more generally to understand how mechanisms of enhancer action influence their composition and evolution.

Dataset Information

Transcription Factor Binding Site Enrichment Analysis in Co-Expression Modules in Celiac Disease.

Publications

Transcription Factor Binding Site Enrichment Analysis in Co-Expression Modules in Celiac Disease.

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