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

• Published in: Nature communications Vol. 10; no. 1; pp. 3477 - 16
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.08.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45/100; 45/15; 45/91; 631/114/2114; 631/532; 631/532/2064/2158; 631/532/2435; Accessibility; Animals; Binding; Binding sites; Cells, Cultured; Cellular Reprogramming - genetics; Chromatin; Chromatin - metabolism; Dependence; Developmental biology; Dimerization; Embryo, Mammalian; Enhancers; Epithelial-Mesenchymal Transition - genetics; Fibroblasts; Gene expression; Genomes; Humanities and Social Sciences; Induced Pluripotent Stem Cells - physiology; KLF4 protein; Laboratories; Medicine; Mesenchyme; Mice, Transgenic; multidisciplinary; Mutation; Oct-4 protein; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Octamer Transcription Factor-6 - metabolism; Pluripotency; Primary Cell Culture; Protein Multimerization - genetics; Science; Science (multidisciplinary); SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Stem cells; Time Factors; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11054-7

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. Oct4, along with Sox2 and Klf4 can induce pluripotency, but structurally similar factors like Oct6 cannot. Here, using pluripotency competent and incompetent factors, the authors show that Sox2 plays a dominant role in facilitating chromatin opening at Oct4 bound DNA early during reprogramming to pluripotency.