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Article

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

by
Irati Romero-Garmendia
1,
Koldo Garcia-Etxebarria
1,†,
Hector Hernandez-Vargas
2,
Izortze Santin
1,3,
Amaia Jauregi-Miguel
1,
Leticia Plaza-Izurieta
1,
Marie-Pierre Cros
2,
Maria Legarda
4,
Iñaki Irastorza
4,
Zdenko Herceg
2,
Nora Fernandez-Jimenez
1,2,* and
Jose Ramon Bilbao
1,3,*
1
University of the Basque Country (UPV-EHU) and Biocruces Health Research Institute, 48940 Leioa, Spain
2
Epigenetics Group, International Agency for Research on Cancer (IARC), 69372 Lyon CEDEX 08, France
3
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain
4
Pediatric Gastroenterology Unit, Cruces University Hospital, University of the Basque Country-(UPV/EHU) and Biocruces Health Research Institute, 48903 Barakaldo, Spain
*
Authors to whom correspondence should be addressed.
†
Current address: Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, 20014 San Sebastian, Spain.
Genes 2018, 9(5), 245; https://doi.org/10.3390/genes9050245
Submission received: 18 April 2018 / Revised: 7 May 2018 / Accepted: 8 May 2018 / Published: 10 May 2018
(This article belongs to the Section Human Genomics and Genetic Diseases)
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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.
Keywords: celiac disease; complex disease; co-expression; gene regulation; transcription factor celiac disease; complex disease; co-expression; gene regulation; transcription factor

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MDPI and ACS Style

Romero-Garmendia, I.; Garcia-Etxebarria, K.; Hernandez-Vargas, H.; Santin, I.; Jauregi-Miguel, A.; Plaza-Izurieta, L.; Cros, M.-P.; Legarda, M.; Irastorza, I.; Herceg, Z.; et al. Transcription Factor Binding Site Enrichment Analysis in Co-Expression Modules in Celiac Disease. Genes 2018, 9, 245. https://doi.org/10.3390/genes9050245

AMA Style

Romero-Garmendia I, Garcia-Etxebarria K, Hernandez-Vargas H, Santin I, Jauregi-Miguel A, Plaza-Izurieta L, Cros M-P, Legarda M, Irastorza I, Herceg Z, et al. Transcription Factor Binding Site Enrichment Analysis in Co-Expression Modules in Celiac Disease. Genes. 2018; 9(5):245. https://doi.org/10.3390/genes9050245

Chicago/Turabian Style

Romero-Garmendia, Irati, Koldo Garcia-Etxebarria, Hector Hernandez-Vargas, Izortze Santin, Amaia Jauregi-Miguel, Leticia Plaza-Izurieta, Marie-Pierre Cros, Maria Legarda, Iñaki Irastorza, Zdenko Herceg, and et al. 2018. "Transcription Factor Binding Site Enrichment Analysis in Co-Expression Modules in Celiac Disease" Genes 9, no. 5: 245. https://doi.org/10.3390/genes9050245

APA Style

Romero-Garmendia, I., Garcia-Etxebarria, K., Hernandez-Vargas, H., Santin, I., Jauregi-Miguel, A., Plaza-Izurieta, L., Cros, M.-P., Legarda, M., Irastorza, I., Herceg, Z., Fernandez-Jimenez, N., & Bilbao, J. R. (2018). Transcription Factor Binding Site Enrichment Analysis in Co-Expression Modules in Celiac Disease. Genes, 9(5), 245. https://doi.org/10.3390/genes9050245

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