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

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. SchwartzJon S. Odorico, Simone Sidoli, Christopher V. Wright, Christina S. Leslie, Danwei Huangfu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1064-1076
Number of pages13
JournalNature Cell Biology
Volume24
Issue number7
DOIs
StatePublished - Jul 2022

ASJC Scopus subject areas

  • Cell Biology

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