Counteracting activities of OCT4 and KLF4 during reprogramming to pluripotency

Ulf Tiemann; Adele Gabriele Marthaler; Kenjiro Adachi; Guangming Wu; Gerrit Ulf Lennart Fischedick; Marcos Jesús Araúzo-Bravo; Hans Robert Schöler; Natalia Tapia

doi:10.1016/j.stemcr.2014.01.005

Counteracting activities of OCT4 and KLF4 during reprogramming to pluripotency

Stem Cell Reports. 2014 Feb 20;2(3):351-65. doi: 10.1016/j.stemcr.2014.01.005. eCollection 2014 Mar 11.

Authors

Ulf Tiemann¹, Adele Gabriele Marthaler¹, Kenjiro Adachi¹, Guangming Wu¹, Gerrit Ulf Lennart Fischedick¹, Marcos Jesús Araúzo-Bravo¹, Hans Robert Schöler¹, Natalia Tapia¹

Affiliation

¹ Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Binding Sites
Bone Marrow Cells / cytology
Bone Marrow Cells / metabolism
Cell Transdifferentiation
Cellular Reprogramming*
Cluster Analysis
Embryonic Stem Cells / cytology
Embryonic Stem Cells / metabolism
Eye Proteins / genetics
Eye Proteins / metabolism
Fibroblasts / metabolism
Gene Expression Profiling
Gene Expression Regulation, Developmental
Induced Pluripotent Stem Cells*
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / chemistry
Kruppel-Like Transcription Factors / classification
Kruppel-Like Transcription Factors / metabolism*
Mice
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism
Neural Stem Cells / cytology
Neural Stem Cells / metabolism
Nucleotide Motifs
Octamer Transcription Factor-3 / chemistry
Octamer Transcription Factor-3 / classification
Octamer Transcription Factor-3 / metabolism*
Organ Specificity
Protein Binding
Transcriptome

Substances

Eye Proteins
Klf4 protein, mouse
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
MGARP protein, mouse
Mitochondrial Proteins
Octamer Transcription Factor-3