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SMAD1 and SMAD5 expression is coordinately regulated by FLI1 and GATA2 during endothelial development

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dc.contributor.authorMarks-Bluth, J.
dc.contributor.authorKhanna, A.
dc.contributor.authorChandrakanthan, V.
dc.contributor.authorThoms, J.
dc.contributor.authorBee, T.
dc.contributor.authorEich, C.
dc.contributor.authorKang, Y.C.
dc.contributor.authorKnezevic, K.
dc.contributor.authorQiao, Q.
dc.contributor.authorFitch, S.
dc.contributor.authorOxburgh, L.
dc.contributor.authorOttersbach, K.
dc.contributor.authorDzierzak, E.
dc.contributor.authorde Bruijn, M.F.T.R.
dc.contributor.authorPimanda, J.E.
dc.date.issued2015
dc.description.abstractThe bone morphogenetic protein (BMP)/SMAD signaling pathway is a critical regulator of angiogenic sprouting and is involved in vascular development in the embryo. SMAD1 and SMAD5, the core mediators of BMP signaling, are vital for this activity, yet little is known about their transcriptional regulation in endothelial cells. Here, we have integrated multispecies sequence conservation, tissue-specific chromatin, in vitro reporter assay, and in vivo transgenic data to identify and validate Smad1+63 and the Smad5 promoter as tissue-specific cis-regulatory elements that are active in the developing endothelium. The activity of these elements in the endothelium was dependent on highly conserved ETS, GATA, and E-box motifs, and chromatin immunoprecipitation showed high levels of enrichment of FLI1, GATA2, and SCL at these sites in endothelial cell lines and E11 dorsal aortas in vivo. Knockdown of FLI1 and GATA2 but not SCL reduced the expression of SMAD1 and SMAD5 in endothelial cells in vitro. In contrast, CD31⁺ cKit‾ endothelial cells harvested from embryonic day 9 (E9) aorta-gonad-mesonephros (AGM) regions of GATA2 null embryos showed reduced Smad1 but not Smad5 transcript levels. This is suggestive of a degree of in vivo selection where, in the case of reduced SMAD1 levels, endothelial cells with more robust SMAD5 expression have a selective advantage.
dc.description.statementofresponsibilityJonathon Marks-Bluth, Anchit Khanna, Vashe Chandrakanthan, Julie Thoms, Thomas Bee, Christina Eich, Young Chan Kang, Kathy Knezevic, Qiao Qiao, Simon Fitch, Leif Oxburgh, Katrin Ottersbach, Elaine Dzierzak, Marella F. T. R. de Bruijn, John E. Pimanda
dc.identifier.citationMolecular and Cellular Biology, 2015; 35(12):2165-2172
dc.identifier.doi10.1128/MCB.00239-15
dc.identifier.issn1098-5549
dc.identifier.issn1098-5549
dc.identifier.orcidChandrakanthan, V. [0000-0002-4314-5029]
dc.identifier.urihttps://hdl.handle.net/2440/145951
dc.language.isoen
dc.publisherTaylor and Francis Group
dc.relation.grantNHMRC
dc.rights© 2015, American Society for Microbiology. All Rights Reserved.
dc.source.urihttps://doi.org/10.1128/mcb.00239-15
dc.subjectGATA2 Transcription Factor; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Promoter Regions, Genetic; Proto-Oncogene Protein c-fli-1; Smad1 Protein; Smad5 Protein; Endothelium; Cell Line; Base Sequence; bone morphogenetic protein (BMP)/SMAD signaling pathway
dc.subject.meshEndothelium
dc.subject.meshCell Line
dc.subject.meshAnimals
dc.subject.meshMice
dc.subject.meshGene Expression Regulation, Developmental
dc.subject.meshBase Sequence
dc.subject.meshMolecular Sequence Data
dc.subject.meshGATA2 Transcription Factor
dc.subject.meshProto-Oncogene Protein c-fli-1
dc.subject.meshSmad1 Protein
dc.subject.meshSmad5 Protein
dc.subject.meshPromoter Regions, Genetic
dc.subject.meshGene Knockdown Techniques
dc.titleSMAD1 and SMAD5 expression is coordinately regulated by FLI1 and GATA2 during endothelial development
dc.typeJournal article
pubs.publication-statusPublished

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