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

Development
Laura A GalvisMarie-Liesse Asselin-Labat

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 lung...Continue Reading

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Citations

Oct 21, 2015·Genomics Data·Aliaksei Z HolikMarie-Liesse Asselin-Labat
Apr 12, 2016·Journal of Cellular Physiology·Ivan Bertoncello
Jun 18, 2017·Development·Changfu YaoBarry R Stripp
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Datasets Mentioned

BETA
GSE10246
GSE57391
GSE57392

Methods Mentioned

BETA
RNA-seq
flow cytometry
ChIP-seq

Software Mentioned

Imaris
Tree Surveyor
Bioconductor
ImageJ Macros
Surfaces
csaw
FIJI
TREAT
Rsubread

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