title: OCT4 Acts as an Integrator of Pluripotency and Signal-Induced Differentiation.
abstract: Cell type specification relies on the capacity of undifferentiated cells to properly respond to specific differentiation-inducing signals. Using genomic approaches along with loss- and gain-of-function genetic models, we identified OCT4-dependent mechanisms that provide embryonic stem cells with the means to customize their response to external cues. OCT4 binds a large set of low-accessible genomic regions. At these sites, OCT4 is required for proper enhancer and gene activation by recruiting co-regulators and RAR:RXR or β-catenin, suggesting an unexpected collaboration between the lineage-determining transcription factor and these differentiation-initiating, signal-dependent transcription factors. As a proof of concept, we demonstrate that overexpression of OCT4 in a kidney cell line is sufficient for signal-dependent activation of otherwise unresponsive genes in these cells. Our results uncover OCT4 as an integral and necessary component of signal-regulated transcriptional processes required for tissue-specific responses.
authors: Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
authors: Zoltan
authors: Z
authors: Simandi
authors: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
authors: Attila
authors: A
authors: Horvath
authors: Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, UK.
authors: Lyndsey C
authors: LC
authors: Wright
authors: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
authors: Ixchelt
authors: I
authors: Cuaranta-Monroy
authors: Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
authors: Isabella
authors: I
authors: De Luca
authors: Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
authors: Katalin
authors: K
authors: Karolyi
authors: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; CU Systems Medicine, University of Würzburg, 97070 Würzburg, Germany; Max Delbrück Center for Molecular Medicine (BISMB and BIH), 13125 Berlin, Germany.
authors: Sascha
authors: S
authors: Sauer
authors: Centre National de Génotypage, Institut de Génomique, CEA, 91000 Evry, France.
authors: Jean-Francois
authors: JF
authors: Deleuze
authors: Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors: Lorraine J
authors: LJ
authors: Gudas
authors: Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, UK.
authors: Shaun M
authors: SM
authors: Cowley
authors: Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; MTA-DE "Lendulet" Immunogenomics Research Group, University of Debrecen, 4032 Debrecen, Hungary. Electronic address: lnagy@sbpdiscovery.org.
authors: Laszlo
authors: L
authors: Nagy
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D065150:Cellular Reprogramming; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D000072482:Retinoic Acid Receptor alpha / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014212:Tretinoin
keywords: Cdx1; Hoxb1; Oct4; RAR:RXR; Wnt/β-catenin; embryonic stem cell; retinoic acid