Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung

Galvis, LA; Holik, AZ; Short, KM; Pasquet, J; Lun, AT; Blewitt, ME; Smyth, IM; Ritchie, ME; Asselin-Labat, ML

Author(s): Galvis, LA; Holik, AZ; Short, KM; Pasquet, J; Lun, AT; Blewitt, ME; Smyth, IM; Ritchie, ME; Asselin-Labat, ML;
Details: Publication Year 2015-04-15,Volume 142,Issue #8,Page 1458-69
Journal Title: Development
Publication Type: Journal Article
Abstract: Epigenetic mechanisms involved in the establishment of lung epithelial cell lineage identities during development are largely unknown. Here, we explored the role of the histone methyltransferase Ezh2 during lung lineage determination. Loss of Ezh2 in the lung epithelium leads to defective lung formation and perinatal mortality. We show that Ezh2 is crucial for airway lineage specification and alveolarization. Using optical projection tomography imaging, we found that branching morphogenesis is affected in Ezh2 conditional knockout mice and the remaining bronchioles are abnormal, lacking terminally differentiated secretory club cells. Remarkably, RNA-seq analysis revealed the upregulation of basal genes in Ezh2-deficient epithelium. Three-dimensional imaging for keratin 5 further showed the unexpected presence of a layer of basal cells from the proximal airways to the distal bronchioles in E16.5 embryos. ChIP-seq analysis indicated the presence of Ezh2-mediated repressive marks on the genomic loci of some but not all basal genes, suggesting an indirect mechanism of action of Ezh2. We found that loss of Ezh2 de-represses insulin-like growth factor 1 (Igf1) expression and that modulation of IGF1 signaling ex vivo in wild-type lungs could induce basal cell differentiation. Altogether, our work reveals an unexpected role for Ezh2 in controlling basal cell fate determination in the embryonic lung endoderm, mediated in part by repression of Igf1 expression.
Publisher: COB
Research Division(s): Stem Cells And Cancer; Bioinformatics; Molecular Medicine
PubMed ID: 25790853
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392602/
Publisher's Version: https://doi.org/10.1242/dev.122077
Open Access at Publisher's Site: http://dev.biologists.org/content/142/8/1458.long
NHMRC Grants: NHMRC/1079756,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-05-20 10:11:20

Last Modified: 2015-05-20 12:00:14