@article{08d4d92009404d1e8df3245d5a604a7a,
title = "CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction",
abstract = "The pancreas and liver arise from a common pool of progenitors. However, the underlying mechanisms that drive their lineage diversification from the foregut endoderm are not fully understood. To tackle this question, we undertook a multifactorial approach that integrated human pluripotent-stem-cell-guided differentiation, genome-scale CRISPR–Cas9 screening, single-cell analysis, genomics and proteomics. We discovered that HHEX, a transcription factor (TF) widely recognized as a key regulator of liver development, acts as a gatekeeper of pancreatic lineage specification. HHEX deletion impaired pancreatic commitment and unleashed an unexpected degree of cellular plasticity towards the liver and duodenum fates. Mechanistically, HHEX cooperates with the pioneer TFs FOXA1, FOXA2 and GATA4, shared by both pancreas and liver differentiation programmes, to promote pancreas commitment, and this cooperation restrains the shared TFs from activating alternative lineages. These findings provide a generalizable model for how gatekeeper TFs like HHEX orchestrate lineage commitment and plasticity restriction in broad developmental contexts.",
author = "Dapeng Yang and Hyunwoo Cho and Zakieh Tayyebi and Abhijit Shukla and Renhe Luo and Gary Dixon and Valeria Ursu and Stephanie Stransky and Tremmel, {Daniel M.} and Sackett, {Sara D.} and Richard Koche and Kaplan, {Samuel J.} and Li, {Qing V.} and Jiwoon Park and Zengrong Zhu and Rosen, {Bess P.} and Julian Pulecio and Shi, {Zhong Dong} and Yaron Bram and Schwartz, {Robert E.} and Odorico, {Jon S.} and Simone Sidoli and Wright, {Christopher V.} and Leslie, {Christina S.} and Danwei Huangfu",
note = "Funding Information: We thank H. Lickert, K. Yang, S. S. Kim, J. Kazakov and N. Zhang for assisting with additional experiments not included in the manuscript; Z. Bao, S. Chen and L. Studer for insightful discussions; N. Verma and F. C. Pan for critical reading and editing of the manuscript; and M. Ray and B. Jarvis for technical support. This study was supported in part by grants to D.H. from DoD PRMRP (W81XWH-20-1-0298), the NIH (R01DK096239, U01HG012051) and the American Diabetes Association (1-19-IBS-125); grants to C.V.W. from the NIH (UC4DK104211, UC4DK108120) and the Leona M. and Harry B. Helmsley Charitable Trust; grants to J.S.O. and D.H. from JDRF (3-SRA-2021-1060-S-B) and DoD PRMRP (W81XWH-20-1-0670); and the University of Wisconsin-Madison, Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation. S. Stransky and S. Sidoli were supported by the Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant), AFAR (Sagol Network GerOmics award), Deerfield (Xseed award) and the NIH Office of the Director (1S10OD030286-01). This study was also supported by a MSKCC Cancer Center Support Grant from the NIH (P30CA008748), a postdoctoral fellowship from a NYSTEM training grant (DOH01-TRAIN3-2015-2016-00006 to D.Y.), NIH T32 Training Grants (T32HD060600 to G.D. and T32GM008539 to S.J.K. and B.P.R.), and a Frank Lappin Horsfall Jr Fellowship (to G.D.). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = jul,
doi = "10.1038/s41556-022-00946-4",
language = "English (US)",
volume = "24",
pages = "1064--1076",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "7",
}