SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling
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The balance between self-renewal and differentiation in human foetal lung epithelial progenitors controls the size and function of the adult organ. Moreover, progenitor cell gene regulation networks are employed by both regenerating and malignant lung cells, where modulators of their effects could potentially be of therapeutic value. Details of the molecular networks controlling human lung progenitor self-renewal remain unknown. We performed the first CRISPRi screen in primary human lung organoids to identify transcription factors controlling progenitor self-renewal. We show that SOX9 promotes proliferation of lung progenitors and inhibits precocious airway differentiation. Moreover, by identifying direct transcriptional targets using Targeted DamID, we place SOX9 at the centre of a transcriptional network, which amplifies WNT and RTK signalling to stabilise the progenitor cell state. In addition, the proof-of-principle CRISPRi screen and Targeted DamID tools establish a new workflow for using primary human organoids to elucidate detailed functional mechanisms underlying normal development and disease.
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Some CRISPR methods have been tested on a small scale but have not yet been fully adopted for large-scale screens in tissue-derived organoids.
“While some of these methods have been tested on a small scale35,36, they have not yet been fully adopted for large-scale screens in tissue-derived organoids.”
From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [36]
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- Authors
- Sun, D., Llora Batlle, O., van den Ameele, J., Thomas, J. C., He, P., Lim, K., Tang, W., Xu, C., Meyer, K. B., Teichmann, S. A., Marioni, J. C., Jackson, S. P., Brand, A. H., & Rawlins, E. L.
- Affiliations
- University of Cambridge (GB)
- European Bioinformatics Institute (GB)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Rawlins, Emma L
- ORCID
- Venue
- The EMBO Journal
- Published
- 2022-09-19
- Volume
- 41
- Issue
- 21
- Pages
- e111338-e111338
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC9627674
- OpenAlex
- W4296322355
- Cited by
- 38
- References
- 66
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 8 · 2023: 9 · 2022: 2
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The EMBO Journal (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo
- Apollo (cc-by)
- Funders
- Cancer Research UK (DRCPGM\100005, C6946/A14492)
- EC¦ERC¦HORIZON EUROPE European Research Council (855741 (DDREAMM))
- National Research Foundation of Korea (2018R1A6A3A03012122)
- Royal Society
- UKRI¦Medical Research Council (MR/P009581/1, MR/S035907/1)
- University of Cambridge¦St. Edmund's College, University of Cambridge
- Wellcome Trust (109146/Z/15/Z, WT211276/Z/18/Z, 103792, 105839, WT206194, 206388/Z/17/Z, 203144/Z/16/Z)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- SOX9, lung progenitor cells, self-renewal, Wnt signaling, transcriptional regulatory networks, lung organoids, CRISPRi screen, transcription factors
- MeSH terms
- Cell Differentiation, Humans, Lung, Stem Cells, Signal Transduction, SOX9 Transcription Factor
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