title: Counteracting activities of OCT4 and KLF4 during reprogramming to pluripotency.
abstract: Differentiated cells can be reprogrammed into induced pluripotent stem cells (iPSCs) after overexpressing four transcription factors, of which Oct4 is essential. To elucidate the role of Oct4 during reprogramming, we investigated the immediate transcriptional response to inducible Oct4 overexpression in various somatic murine cell types using microarray analysis. By downregulating somatic-specific genes, Oct4 induction influenced each transcriptional program in a unique manner. A significant upregulation of pluripotent markers could not be detected. Therefore, OCT4 facilitates reprogramming by interfering with the somatic transcriptional network rather than by directly initiating a pluripotent gene-expression program. Finally, Oct4 overexpression upregulated the gene Mgarp in all the analyzed cell types. Strikingly, Mgarp expression decreases during the first steps of reprogramming due to a KLF4-dependent inhibition. At later stages, OCT4 counteracts the repressive activity of KLF4, thereby enhancing Mgarp expression. We show that this temporal expression pattern is crucial for the efficient generation of iPSCs.
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Tiemann
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
authors.forename: Adele Gabriele
authors.initials: AG
authors.lastname: Marthaler
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Adachi
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
authors.forename: Guangming
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
authors.forename: Gerrit Ulf Lennart
authors.initials: GU
authors.lastname: Fischedick
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
authors.forename: Marcos Jesús
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
authors.forename: Hans Robert
authors.initials: HR
authors.lastname: Schöler
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tapia
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming; D016000:Cluster Analysis; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D057026:Induced Pluripotent Stem Cells; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D059372:Nucleotide Motifs; D050814:Octamer Transcription Factor-3 / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D009928:Organ Specificity; D011485:Protein Binding; D059467:Transcriptome
chemical_list: D005136:Eye Proteins; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C509731:MGARP protein, mouse; D024101:Mitochondrial Proteins; D050814:Octamer Transcription Factor-3