New Insights into FoxE1 Functions: Identification of Direct FoxE1 Targets in Thyroid Cells
Open Access
- 13 May 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (5), e62849
- https://doi.org/10.1371/journal.pone.0062849
Abstract
FoxE1 is a thyroid-specific forkhead transcription factor essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in adults. FoxE1 recognizes and binds to a short DNA sequence present in thyroglobulin (Tg) and thyroperoxidase (Tpo) promoters, but FoxE1 binding to regulatory regions other than Tg and Tpo promoters remains almost unexplored. Improving knowledge of the regulatory functions of FoxE1 is necessary to clarify its role in endocrine syndromes and cancer susceptibility. In order to further investigate downstream FoxE1 targets, we performed a genome-wide expression screening after knocking-down FoxE1 and obtained new insights into FoxE1 transcriptional networks in thyroid follicular cells. After validation, we confirmed Adamts9, Cdh1, Duox2 and S100a4 as upregulated genes and Casp4, Creld2, Dusp5, Etv5, Hsp5a, Nr4a2 and Tm4sf1 as downregulated genes when FoxE1 was silenced. In promoter regions of putative FoxE1-regulated genes and also in the promoters of the classical thyroid genes Nis, Pax8 and Titf1, we performed an in silico search of the FoxE1 binding motif that was in close proximity to the NF1/CTF binding sequence, as previously described for other forkhead factors. Using chromatin immunoprecipitation we detected specific in vivo FoxE1 binding to novel regulatory regions in two relevant thyroid genes, Nis and Duox2. Moreover, we demonstrated simultaneous binding of FoxE1 and NF1/CTF to the Nis upstream enhancer region, as well as a clear functional activation of the Nis promoter by both transcription factors. In search for potential downstream mediators of FoxE1 function in thyroid cells, we identified two novel direct FoxE1 target genes. To our knowledge, this is the first evidence regarding the implication of Nis and Duox2 in executing the transcriptional program triggered by FoxE1. Furthermore, this study points out the important role of FoxE1 in the regulation of a large number of genes in thyroid cells.Keywords
This publication has 51 references indexed in Scilit:
- Genome-wide analysis of Pax8 binding provides new insights into thyroid functionsBMC Genomics, 2012
- Nuclear ReceptorsNur77andNurr1Modulate Mesenchymal Stromal Cell MigrationStem Cells and Development, 2012
- Pioneer transcription factors: establishing competence for gene expressionGenes & Development, 2011
- Babelomics: an integrative platform for the analysis of transcriptomics, proteomics and genomic data with advanced functional profilingNucleic Acids Research, 2010
- The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription FactorsPLoS Genetics, 2009
- Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populationsNature Genetics, 2009
- Genetic and Epigenetic Alterations of Familial Pancreatic CancersCancer Epidemiology, Biomarkers & Prevention, 2008
- The Forkhead Factor FoxE1 Binds to the Thyroperoxidase Promoter during Thyroid Cell Differentiation and Modifies Compacted Chromatin StructureMolecular and Cellular Biology, 2007
- FatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experimentsNucleic Acids Research, 2007
- Thyroid Oxidase (THOX2) Gene Expression in the Rat Thyroid Cell Line FRTL-5Biochemical and Biophysical Research Communications, 2000