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

Malik, Vikas, Glaser, Laura V., Zimmer, Dennis, Velychko, Sergiy, Weng, Mingxi, Holzner, Markus, Arend, Marius, Chen, Yanpu, Srivastava, Yogesh, Veerapandian, Veeramohan, Shah, Zahir, Esteban, Miguel A., Wang, Huating, Chen, Jiekai, Schöler, Hans R., Hutchins, Andrew P., Meijsing, Sebastiaan H., Pott, Sebastian, Jauch, Ralf·2019·Nature Communications
DOI 10.1038/s41467-019-11054-7PMC PMC6677745
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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 (Oct4 defSox2). 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 Oct4 defSox2 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 Oct4 defSox2 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.

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Metadata

Authors
Malik, V., Glaser, L. V., Zimmer, D., Velychko, S., Weng, M., Holzner, M., Arend, M., Chen, Y., Srivastava, Y., Veerapandian, V., Shah, Z., Esteban, M. A., Wang, H., Chen, J., Schöler, H. R., Hutchins, A. P., Meijsing, S. H., Pott, S., & Jauch, R.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-08-02
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-11054-7
PMC
PMC6677745
Cited by
72
References
10
Language
en
Licence
Funders
  • National Natural Science Foundation of China (31471238, 31771454, 31611130038)
  • Chinese Ministry of Science and Technology | Department of S and T for Social Development (2016YFA0100700)

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