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Nat Genet. 2019 Jun;51(6):999-1010. doi: 10.1038/s41588-019-0408-9. Epub 2019 May 20.

Genome-scale screens identify JNK-JUN signaling as a barrier for pluripotency exit and endoderm differentiation.

Author information

1
Sloan Kettering Institute, New York, NY, USA.
2
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Weill Graduate School of Medical Sciences at Cornell University, New York, NY, USA.
4
Weill Graduate School of Medical Sciences at Cornell University/The Rockefeller University/Sloan Kettering Institute Tri-Institutional MD-PhD Program, New York, NY, USA.
5
Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
6
Department of Histo-Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
7
Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
8
Department of Medicine and Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA.
9
Department of Biomedical Engineering and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA. mbeer@jhu.edu.
10
Sloan Kettering Institute, New York, NY, USA. huangfud@mskcc.org.

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.

PMID:
31110351
PMCID:
PMC6545159
[Available on 2019-11-20]
DOI:
10.1038/s41588-019-0408-9

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