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.
Highlights
In the mouse embryonic lung, an epithelial hierarchy has been proposed where multi-lineage progenitor cells give rise to the mature lung epithelial cells (Alanis et al, 2014)
We found that IGF1, a growth factor that is highly upregulated in Ezh2-depleted lung, induces basal cell differentiation ex vivo in wild-type lungs
Our results demonstrate that Ezh2 is crucial for embryonic lung development and further reveal that Ezh2 tightly regulates epithelial cell lineage determination in the developing lung, consistent with its role in maintaining tissue specificity in other organs
Summary
In the mouse embryonic lung, an epithelial hierarchy has been proposed where multi-lineage progenitor cells give rise to the mature lung epithelial cells (Alanis et al, 2014). From E16.5, alveolar type 1 and type 2 cells arise from bipotent alveolar progenitor cells. Studies to identify transcription factors and signaling pathways that drive branching morphogenesis and lineage specification have shown that lung morphogenesis is orchestrated by intrinsic epithelial signaling pathways as well as crosstalk between the epithelium and the mesenchyme (Hogan et al, 2014; Rock and Hogan, 2011). Epigenetic mechanisms that control lung development, maintenance of cell fate and lineage specification remain largely uncharacterized
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