title: TFII-I regulates target genes in the PI-3K and TGF-β signaling pathways through a novel DNA binding motif.
abstract: General transcription factor (TFII-I) is a multi-functional protein involved in the transcriptional regulation of critical developmental genes, encoded by the GTF2I gene located on chromosome 7q11.23. Haploinsufficiency at GTF2I has been shown to play a major role in the neurodevelopmental features of Williams-Beuren syndrome (WBS). Identification of genes regulated by TFII-I is thus critical to detect molecular determinants of WBS as well as to identify potential new targets for specific pharmacological interventions, which are currently absent. We performed a microarray screening for transcriptional targets of TFII-I in cortex and embryonic cells from Gtf2i mutant and wild-type mice. Candidate genes with altered expression were verified using real-time PCR. A novel motif shared by deregulated genes was found and chromatin immunoprecipitation assays in embryonic fibroblasts were used to document in vitro TFII-I binding to this motif in the promoter regions of deregulated genes. Interestingly, the PI3K and TGFβ signaling pathways were over-represented among TFII-I-modulated genes. In this study we have found a highly conserved DNA element, common to a set of genes regulated by TFII-I, and identified and validated novel in vivo neuronal targets of this protein affecting the PI3K and TGFβ signaling pathways. Overall, our data further contribute to unravel the complexity and variability of the different genetic programs orchestrated by TFII-I.
authors.affiliation: Unitat de Genètica, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Segura-Puimedon
authors.forename: Cristina
authors.initials: C
authors.lastname: Borralleras
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pérez-Jurado
authors.forename: Victoria
authors.initials: V
authors.lastname: Campuzano
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D019473:Transcription Factors, TFII / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D019473:Transcription Factors, TFII; D016212:Transforming Growth Factor beta; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases
keywords: CNVs; ChIP; DEG; DNA binding domain; ES; Embryonic stem cells; MEFs; Mouse model; NGF; TFII-I; Transcriptional regulation; WBS; Williams–Beuren syndrome; aCGH; chromatine immunoprecipitation; copy number variants; differentially expressed genes; embryonic stem cells; general transcription factor II-I; microarray comparative genome hybridization; mouse embryonic fibroblast; nerve growth factor; qRT-PCR; quantitative real-time polymerase chain reaction