CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction Journal Article
| Authors: | Yang, D.; Cho, H.; Tayyebi, Z.; Shukla, A.; Luo, R.; Dixon, G.; Ursu, V.; Stransky, S.; Tremmel, D. M.; Sackett, S. D.; Koche, R.; Kaplan, S. J.; Li, Q. V.; Park, J.; Zhu, Z.; Rosen, B. P.; Pulecio, J.; Shi, Z. D.; Bram, Y.; Schwartz, R. E.; Odorico, J. S.; Sidoli, S.; Wright, C. V.; Leslie, C. S.; Huangfu, D. |
| Article 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. © 2022, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | controlled study; human tissue; unclassified drug; human cell; gene deletion; genetics; nonhuman; pancreas; mouse; metabolism; animal tissue; gene; hepatocyte nuclear factor 3alpha; protein protein interaction; transcription factor; cell fate; cell differentiation; homeodomain proteins; cell lineage; transcription factors; gene expression regulation; gene expression regulation, developmental; liver; homeodomain protein; duodenum; endoderm; transcription factor gata 4; hepatocyte nuclear factor 3beta; cell plasticity; liver development; humans; human; male; female; article; clustered regularly interspaced short palindromic repeat; hhex protein; hhex protein, human; hhex gene |
| Journal Title: | Nature Cell Biology |
| Volume: | 24 |
| Issue: | 7 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-07-01 |
| Start Page: | 1064 |
| End Page: | 1076 |
| Language: | English |
| DOI: | 10.1038/s41556-022-00946-4 |
| PUBMED: | 35787684 |
| PROVIDER: | scopus |
| PMCID: | PMC9283336 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
