An organoid CRISPRi screen revealed that SOX9 primes human fetal lung tip progenitors to receive WNT and RTK signals
An organoid CRISPRi screen revealed that SOX9 primes human fetal lung tip progenitors to receive WNT and RTK signals
ABSTRACT The balance between self-renewal and differentiation in human fetal 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 approach for using primary human organoids to elucidate detailed functional mechanisms underlying normal development and disease. HighlightsA pooled CRISPRi screen in human fetal lung organoids identified transcription factors controlling progenitor cell self-renewal.SOX9 promotes tip progenitor cell proliferation and supresses precocious airway differentiation.Targeted DamID (TaDa) identified SOX9 direct binding targets, revealing that SOX9 lies at the intersection of WNT and RTK signalling.SOX9 and ETVs co-regulate the human fetal lung progenitor self-renewal programme.
Tang Walfred、Sun Dawei、He Peng、Xu Chufan、Teichmann Sarah A.、Jackson Stephen P.、Rawlins Emma L.、van den Ameele Jelle、Batlle Oriol Llora、Marioni John C.、Meyer Kerstin B.、Thomas John C.、Lim Kyungtae、Brand Andrea H.
Wellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Physiology, Development and Neuroscience, University of CambridgeWellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Physiology, Development and Neuroscience, University of CambridgeWellcome Sanger Institute||European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome CampusWellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Anaesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of MedicineWellcome Sanger Institute||Department of Physics/Cavendish Laboratory, University of CambridgeWellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Biochemistry, University of CambridgeWellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Physiology, Development and Neuroscience, University of CambridgeWellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Physiology, Development and Neuroscience, University of Cambridge||Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of CambridgeWellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Physiology, Development and Neuroscience, University of CambridgeWellcome Sanger Institute||European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus||Cancer Research UK Cambridge Institute, University of CambridgeWellcome Sanger InstituteWellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Biochemistry, University of CambridgeWellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Physiology, Development and Neuroscience, University of CambridgeWellcome Trust/CRUK Gurdon Institute, University of Cambridge||Department of Physiology, Development and Neuroscience, University of Cambridge
基础医学生物科学研究方法、生物科学研究技术分子生物学
Tang Walfred,Sun Dawei,He Peng,Xu Chufan,Teichmann Sarah A.,Jackson Stephen P.,Rawlins Emma L.,van den Ameele Jelle,Batlle Oriol Llora,Marioni John C.,Meyer Kerstin B.,Thomas John C.,Lim Kyungtae,Brand Andrea H..An organoid CRISPRi screen revealed that SOX9 primes human fetal lung tip progenitors to receive WNT and RTK signals[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2022.01.27.478034.点此复制
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