NKX3-1 is required for induced pluripotent stem cell reprogramming and can replace OCT4 in mouse and human iPSC induction.

Nature Cell Biology
Thach MaiHelen M Blau

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.

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Citations

Apr 17, 2020·PLoS Pathogens·Theofano PanayiotouKaterina Strati
Aug 12, 2020·Cellular Reprogramming·Érika Almeida PraxedesAlexsandra Fernandes Pereira
Aug 19, 2020·Nature Chemical Biology·Kee-Pyo KimHans R Schöler
Sep 13, 2020·Science Advances·Kee-Pyo KimHans R Schöler
Mar 18, 2020·International Journal of Molecular Sciences·Shu NakaoTeruhisa Kawamura
Dec 2, 2020·Nature Biotechnology·Alex H M NgGeorge M Church
Dec 12, 2020·Computational and Structural Biotechnology Journal·Ainsley Mike AntaoSuresh Ramakrishna
Mar 6, 2021·Veterinary Research·Bertrand Pain
Aug 29, 2020·Endocrine Regulations·Dariia O TsymbalOleksandr H Minchenko
Apr 16, 2021·Frontiers in Cellular Neuroscience·Amrita A Iyer, Andrew K Groves
Jun 6, 2021·Proceedings of the National Academy of Sciences of the United States of America·Glenn J MarkovHelen M Blau
Jun 5, 2021·Current Opinion in Genetics & Development·Karen E Brown, Amanda G Fisher
Jun 13, 2021·Experimental & Molecular Medicine·Kee-Pyo KimHans R Schöler

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Datasets Mentioned

BETA
GSE103509
GSE103536
GSE46104

Methods Mentioned

BETA
RNA-seq
immunoprecipitation
PCR
transfection
flow cytometry
fluorescence activated cell sorting
Assay

Software Mentioned

OpenLab
FactoMineR
STAR
ENVIGO
MACS
findMotifsGenome
R
gplots
DESEQ2
Improvision

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