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Cell Syst. 2015 Aug 26;1(2):141-51. doi: 10.1016/j.cels.2015.08.002. Epub 2015 Aug 26.

Systems Analyses Reveal Shared and Diverse Attributes of Oct4 Regulation in Pluripotent Cells.

Author information

1
Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.
2
Genomics, Biotechnology Center, TU Dresden, 01307 Dresden, Germany.
3
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
4
Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
5
The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
6
Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
7
Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
8
Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany. Electronic address: frank.buchholz@tu-dresden.de.

Abstract

We combine a genome-scale RNAi screen in mouse epiblast stem cells (EpiSCs) with genetic interaction, protein localization, and "protein-level dependency" studies-a systematic technique that uncovers post-transcriptional regulation-to delineate the network of factors that control the expression of Oct4, a key regulator of pluripotency. Our data signify that there are similarities, but also fundamental differences in Oct4 regulation in EpiSCs versus embryonic stem cells (ESCs). Through multiparametric data analyses, we predict that Tox4 is associating with the Paf1C complex, which maintains cell identity in both cell types, and validate that this protein-protein interaction exists in ESCs and EpiSCs. We also identify numerous knockdowns that increase Oct4 expression in EpiSCs, indicating that, in stark contrast to ESCs, Oct4 is under active repressive control in EpiSCs. These studies provide a framework for better understanding pluripotency and for dissecting the molecular events that govern the transition from the pre-implantation to the post-implantation state.

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