Abstract
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is now routinely accomplished by overexpression of the four Yamanaka factors (OCT4, SOX2, KLF4, MYC (or OSKM))1. These iPSCs can be derived from patients' somatic cells and differentiated toward diverse fates, serving as a resource for basic and translational research. However, mechanistic insights into regulators and pathways that initiate the pluripotency network remain to be resolved. In particular, naturally occurring molecules that activate endogenous OCT4 and replace exogenous OCT4 in human iPSC reprogramming have yet to be found. Using a heterokaryon reprogramming system we identified NKX3-1 as an early and transiently expressed homeobox transcription factor. Following knockdown of NKX3-1, iPSC reprogramming is abrogated. NKX3-1 functions downstream of the IL-6-STAT3 regulatory network to activate endogenous OCT4. Importantly, NKX3-1 substitutes for exogenous OCT4 to reprogram both mouse and human fibroblasts at comparable efficiencies and generate fully pluripotent stem cells. Our findings establish an essential role for NKX3-1, a prostate-specific tumour suppressor, in iPSC reprogramming.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Cellular Reprogramming Techniques*
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Cellular Reprogramming*
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Gene Expression Regulation, Developmental
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Induced Pluripotent Stem Cells / metabolism*
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Homeodomain Proteins
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IL6 protein, human
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Interleukin-6
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KLF4 protein, human
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Klf4 protein, mouse
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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MYC protein, human
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NKX3-1 protein, human
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Nkx3-1 protein, mouse
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Octamer Transcription Factor-3
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POU5F1 protein, human
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Pou5f1 protein, mouse
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Proto-Oncogene Proteins c-myc
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SOX2 protein, human
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SOXB1 Transcription Factors
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse
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Transcription Factors
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interleukin-6, mouse