Klf4 Interacts Directly with Oct4 and Sox2 to Promote Reprogramming

Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by ectopic expression of specific sets of transcription factors. Oct4, Sox2, and Klf4, factors that share many target genes in embryonic stem (ES) cells, are critical components in various reprogramming protocols. Nevertheless...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2009-12, Vol.27 (12), p.2969-2978
Main Authors: Wei, Zong, Yang, Yang, Zhang, Peilin, Andrianakos, Rosemary, Hasegawa, Kouichi, Lyu, Jungmook, Chen, Xi, Bai, Gang, Liu, Chunming, Pera, Martin, Lu, Wange
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Cellular Reprogramming
Humans
Induced pluripotent stem cells
Induced Pluripotent Stem Cells - metabolism
Kruppel-Like Transcription Factors - genetics
Kruppel-Like Transcription Factors - metabolism
Mice
Mutation
Neural stem cells
Octamer Transcription Factor-3 - genetics
Octamer Transcription Factor-3 - metabolism
Protein Binding
Reprogramming
SOXB1 Transcription Factors - genetics
SOXB1 Transcription Factors - metabolism
Transcriptional factors
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Summary:Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by ectopic expression of specific sets of transcription factors. Oct4, Sox2, and Klf4, factors that share many target genes in embryonic stem (ES) cells, are critical components in various reprogramming protocols. Nevertheless, it remains unclear whether these factors function together or separately in reprogramming. Here we show that Klf4 interacts directly with Oct4 and Sox2 when expressed at levels sufficient to induce iPS cells. Endogenous Klf4 also interacts with Oct4 and Sox2 in iPS cells and in mouse ES cells. The Klf4 C terminus, which contains three tandem zinc fingers, is critical for this interaction and is required for activation of the target gene Nanog. In addition, Klf4 and Oct4 co‐occupy the Nanog promoter. A dominant negative mutant of Klf4 can compete with wild‐type Klf4 to form defective Oct4/Sox2/Klf4 complexes and strongly inhibit reprogramming. In the absence of Klf4 overexpression, interaction of endogenous Klf4 with Oct4/Sox2 is also required for reprogramming. This study supports the idea that direct interactions between Klf4, Oct4, and Sox2 are critical for somatic cell reprogramming. STEM CELLS 2009;27:2969–2978
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.231