Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation
Open accessAbstract
Enteroendocrine cells (EECs) are hormone-producing cells residing in the epithelium of stomach, small intestine (SI), and colon. EECs regulate aspects of metabolic activity, including insulin levels, satiety, gastrointestinal secretion, and motility. The generation of different EEC lineages is not completely understood. In this work, we report a CRISPR knockout screen of the entire repertoire of transcription factors (TFs) in adult human SI organoids to identify dominant TFs controlling EEC differentiation. We discovered ZNF800 as a master repressor for endocrine lineage commitment, which particularly restricts enterochromaffin cell differentiation by directly controlling an endocrine TF network centered on PAX4. Thus, organoid models allow unbiased functional CRISPR screens for genes that program cell fate.
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CRISPR cutting screens in 3D organoids have been implemented to explore factors such as growth factor dependency for cell growth, identify potential cancer-driving forces, and uncover key genetic events in cell differentiation.
“Even more exciting is the implementation of CRISPR cutting screens in 3D organoids to explore factors such as growth factor dependency for cell growth14–16, identifying potential cancer-driving forces17–19, and uncovering key genetic events in cell differentiation20–22.”
From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [21]
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Identification of Enteroendocrine Regulators by Real-Time Single-Cell Differentiation Mapping
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- Authors
- Lin, L., DeMartino, J., Wang, D., van Son, G. J. F., van der Linden, R., Begthel, H., Korving, J., Andersson-Rolf, A., van den Brink, S., Lopez-Iglesias, C., van de Wetering, W. J., Balwierz, A., Margaritis, T., van de Wetering, M., Peters, P. J., Drost, J., van Es, J. H., & Clevers, H.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- Oncode Institute (NL)
- Oncode Institute, Utrecht, Netherlands.
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, Netherlands.
- The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, Netherlands.
- Princess Máxima Center (NL)
- Maastricht University (NL)
- Corresponding author
- Lin, Lin
- Clevers, Hans
- ORCID
- Venue
- Science
- Published
- 2023-10-27
- Volume
- 382
- Issue
- 6669
- Pages
- 451-458
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W4387951835
- Cited by
- 50
- References
- 7
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 15 · 2023: 1
- FWCI
- 4.44
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- Funders
- Brigham and Women's Hospital
- Koninklijke Nederlandse Akademie van Wetenschappen
- Universiteit Maastricht
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (024.003.001, 024.003, 2019.085)
- Oncode Institute
- University of California, San Diego
- H2020 European Research Council (101020405)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- enteroendocrine cells, transcription factors, enterochromaffin cells, Pax4, cell fate specification, CRISPR knockout screen
- MeSH terms
- Adult, Cell Differentiation, Gene Expression Regulation, Humans, Organoids, Repressor Proteins, Zinc Fingers, Cell Lineage, Enteroendocrine Cells, CRISPR-Cas Systems
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