CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction.
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
26
09
2021
accepted:
25
05
2022
pubmed:
6
7
2022
medline:
15
7
2022
entrez:
5
7
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35787684
doi: 10.1038/s41556-022-00946-4
pii: 10.1038/s41556-022-00946-4
pmc: PMC9283336
mid: NIHMS1817654
doi:
Substances chimiques
HHEX protein, human
0
Homeodomain Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1064-1076Subventions
Organisme : NIDDK NIH HHS
ID : UC4 DK104211
Pays : United States
Organisme : NIDDK NIH HHS
ID : UC4 DK108120
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008539
Pays : United States
Organisme : NIH HHS
ID : S10 OD030286
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD060600
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK096239
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020541
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG012051
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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