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. Schwartz; Jon S. Odorico; Simone Sidoli; Christopher V. Wright; Christina S. Leslie; Danwei Huangfu

doi:10.1038/s41556-022-00946-4

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

Biochemistry

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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 language	English (US)
Pages (from-to)	1064-1076
Number of pages	13
Journal	Nature Cell Biology
Volume	24
Issue number	7
DOIs	https://doi.org/10.1038/s41556-022-00946-4
State	Published - Jul 2022

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Cell Biology

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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., ... Huangfu, D. (2022). CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction. Nature Cell Biology, 24(7), 1064-1076. https://doi.org/10.1038/s41556-022-00946-4

Yang, D, Cho, H, Tayyebi, Z, Shukla, A, Luo, R, Dixon, G, Ursu, V, Stransky, S, Tremmel, DM, Sackett, SD, Koche, R, Kaplan, SJ, Li, QV, Park, J, Zhu, Z, Rosen, BP, Pulecio, J, Shi, ZD, Bram, Y, Schwartz, RE, Odorico, JS, Sidoli, S, Wright, CV, Leslie, CS & Huangfu, D 2022, 'CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction', Nature Cell Biology, vol. 24, no. 7, pp. 1064-1076. https://doi.org/10.1038/s41556-022-00946-4

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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",

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AU - Shukla, Abhijit

AU - Luo, Renhe

AU - Dixon, Gary

AU - Ursu, Valeria

AU - Stransky, Stephanie

AU - Tremmel, Daniel M.

AU - Sackett, Sara D.

AU - Koche, Richard

AU - Kaplan, Samuel J.

AU - Li, Qing V.

AU - Park, Jiwoon

AU - Zhu, Zengrong

AU - Rosen, Bess P.

AU - Pulecio, Julian

AU - Shi, Zhong Dong

AU - Bram, Yaron

AU - Schwartz, Robert E.

AU - Odorico, Jon S.

AU - Sidoli, Simone

AU - Wright, Christopher V.

AU - Leslie, Christina S.

AU - Huangfu, Danwei

PY - 2022/7

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N2 - 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.

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

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