Pluripotency reprogramming by competent and incompetent POU factors uncovers temporal dependency for Oct4 and Sox2

Vikas Malik, Laura V. Glaser, Dennis Zimmer, Sergiy Velychko, Mingxi Weng, Markus Holzner, Marius Arend, Yanpu Chen, Yogesh Srivastava, Veeramohan Veerapandian, Zahir Shah, Miguel A. Esteban, Huating Wang, Jiekai Chen, Hans R. Schöler, Andrew P. Hutchins, Sebastiaan H. Meijsing, Sebastian Pott and Ralf Jauch ()
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Vikas Malik: Chinese Academy of Sciences, Guangzhou Medical University
Laura V. Glaser: Max Planck Institute for Molecular Genetics
Dennis Zimmer: Chinese Academy of Sciences, Guangzhou Medical University
Sergiy Velychko: Max Planck Institute for Molecular Biomedicine
Mingxi Weng: The University of Hong Kong
Markus Holzner: The University of Hong Kong
Marius Arend: The University of Hong Kong
Yanpu Chen: Chinese Academy of Sciences, Guangzhou Medical University
Yogesh Srivastava: Chinese Academy of Sciences, Guangzhou Medical University
Veeramohan Veerapandian: Chinese Academy of Sciences, Guangzhou Medical University
Zahir Shah: University of Chinese Academy of Sciences
Miguel A. Esteban: Chinese Academy of Sciences, Guangzhou Medical University
Huating Wang: The Chinese University of Hong Kong
Jiekai Chen: Chinese Academy of Sciences, Guangzhou Medical University
Hans R. Schöler: Max Planck Institute for Molecular Biomedicine
Andrew P. Hutchins: Southern University of Science and Technology
Sebastiaan H. Meijsing: Max Planck Institute for Molecular Genetics
Sebastian Pott: The University of Chicago
Ralf Jauch: Chinese Academy of Sciences, Guangzhou Medical University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Oct4, along with Sox2 and Klf4 (SK), can induce pluripotency but structurally similar factors like Oct6 cannot. To decode why Oct4 has this unique ability, we compare Oct4-binding, accessibility patterns and transcriptional waves with Oct6 and an Oct4 mutant defective in the dimerization with Sox2 (Oct4defSox2). We find that initial silencing of the somatic program proceeds indistinguishably with or without Oct4. Oct6 mitigates the mesenchymal-to-epithelial transition and derails reprogramming. These effects are a consequence of differences in genome-wide binding, as the early binding profile of Oct4defSox2 resembles Oct4, whilst Oct6 does not bind pluripotency enhancers. Nevertheless, in the Oct6-SK condition many otherwise Oct4-bound locations become accessible but chromatin opening is compromised when Oct4defSox2 occupies these sites. We find that Sox2 predominantly facilitates chromatin opening, whilst Oct4 serves an accessory role. Formation of Oct4/Sox2 heterodimers is essential for pluripotency establishment; however, reliance on Oct4/Sox2 heterodimers declines during pluripotency maintenance.

Date: 2019
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DOI: 10.1038/s41467-019-11054-7

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