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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents



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ID: 744137.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
Changing POU dimerization preferences converts Oct6 into a pluripotency inducer
Authors:Jerabek, S.; Ng, C. K.; Wu, G.; Arauzo-Bravo, M. J.; Kim, K. P.; Esch, D.; Malik, V.; Chen, Y.; Velychko, S.; MacCarthy, C. M.; Yang, X.; Cojocaru, V.; Scholer, H. R.; Jauch, R.
Date of Publication (YYYY-MM-DD):2017-02
Title of Journal:EMBO Rep
Volume:18
Issue / Number:2
Start Page:319
End Page:333
Review Status:Internal review
Audience:Not Specified
Abstract / Description:The transcription factor Oct4 is a core component of molecular cocktails inducing pluripotent stem cells (iPSCs), while other members of the POU family cannot replace Oct4 with comparable efficiency. Rather, group III POU factors such as Oct6 induce neural lineages. Here, we sought to identify molecular features determining the differential DNA-binding and reprogramming activity of Oct4 and Oct6. In enhancers of pluripotency genes, Oct4 cooperates with Sox2 on heterodimeric SoxOct elements. By re-analyzing ChIP-Seq data and performing dimerization assays, we found that Oct6 homodimerizes on palindromic OctOct more cooperatively and more stably than Oct4. Using structural and biochemical analyses, we identified a single amino acid directing binding to the respective DNA elements. A change in this amino acid decreases the ability of Oct4 to generate iPSCs, while the reverse mutation in Oct6 does not augment its reprogramming activity. Yet, with two additional amino acid exchanges, Oct6 acquires the ability to generate iPSCs and maintain pluripotency. Together, we demonstrate that cell type-specific POU factor function is determined by select residues that affect DNA-dependent dimerization.
Free Keywords:Amino Acid Substitution; Animals; Binding Sites; Cell Line; Cell Transdifferentiation/*genetics; Cellular Reprogramming/*genetics; Embryonic Stem Cells; Enhancer Elements, Genetic; Epigenesis, Genetic; Humans; Induced Pluripotent Stem Cells/cytology/metabolism; Mice; Models, Molecular; Nucleotide Motifs; Octamer Transcription Factors/chemistry/genetics/metabolism; Organic Cation Transport Proteins/*genetics/*metabolism; POU Domain Factors/*chemistry/genetics/*metabolism; Promoter Regions, Genetic; Protein Binding; Protein Conformation; *Protein Multimerization; Protein Stability; Transcriptome; *DNA binding; *Oct4; *POU factors; *reprogramming to pluripotency
External Publication Status:published
Document Type:Article
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Institute of Medical Biology, Singapore City, Singapore. Biodonostia Health Research Institute, San Sebastian, Spain. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. Genome Regulation Laboratory, Drug Discovery Pipeline, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. Center for Multiscale Theory and Computation, University of Munster, Munster, Germany. Max Planck Institute for Molecular Biomedicine, Munster, Germany office@mpi-muenster.mpg.de ralf@gibh.ac.cn. Medical Faculty, University of Munster, Munster, Germany. Genome Regulation Laboratory, Drug Discovery Pipeline, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China office@mpi-muenster.mpg.de ralf@gibh.ac.cn.
Identifiers:ISSN:1469-3178 (Electronic) 1469-221X (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/28007765 [ID No:2]
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