An organoid-based CRISPR-Cas9 screen for regulators of intestinal epithelial maturation and cell fate.
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Date
2023-07-14ICR Author
Author
Hansen, SL
Larsen, HL
Pikkupeura, LM
Maciag, G
Guiu, J
Müller, I
Clement, DL
Mueller, C
Johansen, JV
Helin, K
Lerdrup, M
Jensen, KB
Type
Journal Article
Metadata
Show full item recordAbstract
Generation of functionally mature organs requires exquisite control of transcriptional programs governing cell state transitions during development. Despite advances in understanding the behavior of adult intestinal stem cells and their progeny, the transcriptional regulators that control the emergence of the mature intestinal phenotype remain largely unknown. Using mouse fetal and adult small intestinal organoids, we uncover transcriptional differences between the fetal and adult state and identify rare adult-like cells present in fetal organoids. This suggests that fetal organoids have an inherent potential to mature, which is locked by a regulatory program. By implementing a CRISPR-Cas9 screen targeting transcriptional regulators expressed in fetal organoids, we establish Smarca4 and Smarcc1 as important factors safeguarding the immature progenitor state. Our approach demonstrates the utility of organoid models in the identification of factors regulating cell fate and state transitions during tissue maturation and reveals that SMARCA4 and SMARCC1 prevent precocious differentiation during intestinal development.
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Subject
Animals
Mice
CRISPR-Cas Systems
Cell Differentiation
Fetus
Adult Stem Cells
Organoids
Research team
CEO Office
Language
eng
Date accepted
2023-06-08
License start date
2023-07-14
Citation
Science Advances, 2023, 9 (28), pp. eadg4055 -
Publisher
AMER ASSOC ADVANCEMENT SCIENCE