Journal
NUCLEIC ACIDS RESEARCH
Volume 43, Issue 9, Pages 4381-4392Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv323
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Funding
- Ministry of Science and Technology of China [2015CB910304, 2015CB964503]
- Hi-Tech Research and Development Program of China [2012AA020302]
- Chinese Academy of Sciences [XDA01040301, XDA01040305]
- National Natural Science Foundation of China [31371511, 81425024, 21210003, 21472208]
- National Science and Technology Major Project 'Key New Drug Creation and Manufacturing Program' [2014ZX09507002, 2013ZX09507-004]
- project of State Key Laboratory of Toxicology and Medical Countermeasures (Academy of Military Medical Science)
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The POU family transcription factor Oct4 plays pivotal roles in regulating pluripotency and somatic cell reprogramming. Previous studies have indicated an important role for major groove contacts in Oct4-DNA recognition; however, the contributions of the RK motif in the POUh domain and the linker segment joining the two DNA-binding domains remain poorly understood. Here, by combining molecular modelling and functional assays, we find that the RK motif is essential for Oct4-DNA association by recognizing the narrowed DNA minor groove. Intriguingly, computational simulations reveal that the function of the RK motif may be finely tuned by H-bond interactions with the partially disordered linker segment and that breaking these interactions significantly enhances the DNA binding and reprogramming activities of Oct4. These findings uncover a self-regulatory mechanism for specific Oct4-DNA recognition and provide insights into the functional crosstalk at the molecular level that may illuminate mechanistic studies of the Oct protein family and possibly transcription factors in the POU family. Our gain-of-function Oct4 mutants might also be useful tools for use in reprogramming and regenerative medicine.
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