@article{b5771fb1ea864477bc688da2fb6bbe1a,
title = "Genome-scale screens identify JNK–JUN signaling as a barrier for pluripotency exit and endoderm differentiation",
abstract = "Human embryonic stem cells (ESCs) and human induced pluripotent stem cells hold great promise for cell-based therapies and drug discovery. However, homogeneous differentiation remains a major challenge, highlighting the need for understanding developmental mechanisms. We performed genome-scale CRISPR screens to uncover regulators of definitive endoderm (DE) differentiation, which unexpectedly uncovered five Jun N-terminal kinase (JNK)–JUN family genes as key barriers of DE differentiation. The JNK–JUN pathway does not act through directly inhibiting the DE enhancers. Instead, JUN co-occupies ESC enhancers with OCT4, NANOG, SMAD2 and SMAD3, and specifically inhibits the exit from the pluripotent state by impeding the decommissioning of ESC enhancers and inhibiting the reconfiguration of SMAD2 and SMAD3 chromatin binding from ESC to DE enhancers. Therefore, the JNK–JUN pathway safeguards pluripotency from precocious DE differentiation. Direct pharmacological inhibition of JNK significantly improves the efficiencies of generating DE and DE-derived pancreatic and lung progenitor cells, highlighting the potential of harnessing the knowledge from developmental studies for regenerative medicine.",
author = "Li, {Qing V.} and Gary Dixon and Nipun Verma and Rosen, {Bess P.} and Miriam Gordillo and Renhe Luo and Chunlong Xu and Qiong Wang and Soh, {Chew Li} and Dapeng Yang and Miguel Crespo and Abhijit Shukla and Qing Xiang and Friederike D{\"u}ndar and Paul Zumbo and Matthew Witkin and Richard Koche and Doron Betel and Shuibing Chen and Joan Massagu{\'e} and Ralph Garippa and Todd Evans and Beer, {Michael A.} and Danwei Huangfu",
note = "Funding Information: The CV iPSC line was a gift from L. Goldstein. We thank Z. Zhu, Z.-D. Shi, I. Caspi and T. Leonardo for technical assistance; S. Mehta for assistance with CRISPR screen HiSeq; Y. Zou for assistance with ChIP-seq analysis; A.-K. Hadjantonakis and S. Tao for assisting with additional experiments not included in the manuscript; and K.V. Anderson, L. Studer, W. Guo, L. Dow and members of D.H.{\textquoteright}s laboratory for insightful discussions. This study was supported in part by New York State Stem Cell Science (NYSTEM; grant nos. C029156 and C32593GG); NIH (grant no. R01DK096239); the MSKCC Cancer Center Support Grant (grant no. P30CA008748); NIH grant no. U01HG009380 (to M.A.B.); NIH grant no. R01HG007348 (to M.A.B.); an NIH T32 Training Grant in Developmental and Stem Cell Biology (grant no. T32HD060600 to G.D.); an NIH T32 Training Grant in Molecular and Cellular Biology (grant no. T32GM008539 to B.P.R.); a Howard Hughes Medical Institute Medical Research Fellowship (to N.V.); and a postdoctoral fellowship from a NYSTEM grant (no. C026879 to Q.W.) to the Center for Stem Cell Biology of the Sloan Kettering Institute and the National Natural Science Foundation of China (grant no. 31771512 to Q.W.). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = jun,
day = "1",
doi = "10.1038/s41588-019-0408-9",
language = "English (US)",
volume = "51",
pages = "999--1010",
journal = "Nature genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",
}