CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2022-07-04

AUTHORS

Dapeng Yang, Hyunwoo Cho, Zakieh Tayyebi, Abhijit Shukla, Renhe Luo, Gary Dixon, Valeria Ursu, Stephanie Stransky, Daniel M. Tremmel, Sara D. Sackett, Richard Koche, Samuel J. Kaplan, Qing V. Li, Jiwoon Park, Zengrong Zhu, Bess P. Rosen, Julian Pulecio, Zhong-Dong Shi, Yaron Bram, Robert E. Schwartz, Jon S. Odorico, Simone Sidoli, Christopher V. Wright, Christina S. Leslie, Danwei Huangfu

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. More... »

PAGES

1064-1076

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  • Journal

    TITLE

    Nature Cell Biology

    ISSUE

    7

    VOLUME

    24

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41556-022-00946-4

    DOI

    http://dx.doi.org/10.1038/s41556-022-00946-4

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1149203125

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/35787684


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