Repository logo
 

SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling.

Published version
Peer-reviewed

Change log

Abstract

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.

Description

Funder: Royal Society (The Royal Society); Id: http://dx.doi.org/10.13039/501100000288


Funder: University of Cambridge¦St. Edmund's College, University of Cambridge (St Edmund's College, University of Cambridge)

Keywords

CRISPRi screen, ETVs, Lung organoids, SOX9, Targeted DamID, Humans, Cell Differentiation, Lung, Signal Transduction, SOX9 Transcription Factor, Stem Cells

Journal Title

EMBO J

Conference Name

Journal ISSN

0261-4189
1460-2075

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (092096/Z/10/Z)
Medical Research Council (MR/P009581/1)
Medical Research Council (MR/S035907/1)
Cancer Research Uk (None)
Wellcome Trust (103792/Z/14/Z)
Wellcome Trust (105839/Z/14/Z)
Wellcome Trust (109146/Z/15/Z)
Wellcome Trust (203144/Z/16/Z)
Wellcome Trust (206388/Z/17/Z)
European Commission Horizon 2020 (H2020) ERC (855741)
Relationships
Is supplemented by: