An organoid-based CRISPR-Cas9 screen for regulators of intestinal epithelial maturation and cell fate
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An organoid-based CRISPR-Cas9 screen for regulators of intestinal epithelial maturation and cell fate. / Hansen, Stine Lind; Larsen, Hjalte L; Pikkupeura, Laura M; Maciag, Grzegorz; Guiu, Jordi; Müller, Iris; Clement, Ditte L; Mueller, Christina; Johansen, Jens Vilstrup; Helin, Kristian; Lerdrup, Mads; Jensen, Kim B.
In: Science Advances, Vol. 9, No. 28, eadg4055, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - An organoid-based CRISPR-Cas9 screen for regulators of intestinal epithelial maturation and cell fate
AU - Hansen, Stine Lind
AU - Larsen, Hjalte L
AU - Pikkupeura, Laura M
AU - Maciag, Grzegorz
AU - Guiu, Jordi
AU - Müller, Iris
AU - Clement, Ditte L
AU - Mueller, Christina
AU - Johansen, Jens Vilstrup
AU - Helin, Kristian
AU - Lerdrup, Mads
AU - Jensen, Kim B
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - CRISPR-Cas Systems
KW - Cell Differentiation/genetics
KW - Fetus
KW - Adult Stem Cells
KW - Organoids
U2 - 10.1126/sciadv.adg4055
DO - 10.1126/sciadv.adg4055
M3 - Journal article
C2 - 37436979
VL - 9
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 28
M1 - eadg4055
ER -
ID: 359615865