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

Laura A. Galvis, Aliaksei Z. Holik, Kieran M. Short, Julie Pasquet, Aaron T.L. Lun, Marnie E. Blewitt, Ian M. Smyth, Matthew E. Ritchie, Marie-Liesse Labat

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Epigeneticmechanisms 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 fromthe 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.

Original languageEnglish (US)
Pages (from-to)1458-1469
Number of pages12
JournalDevelopment (Cambridge)
Volume142
Issue number8
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Somatomedins
Cell Differentiation
Lung
Bronchioles
Epithelium
Optical Tomography
Keratin-5
Endoderm
Three-Dimensional Imaging
Perinatal Mortality
Cell Lineage
Morphogenesis
Knockout Mice
Genes
Up-Regulation
Embryonic Structures
Epithelial Cells
RNA

Keywords

  • Basal cells
  • Ezh2
  • IGF1
  • Lung development
  • Mouse
  • Polycomb repressive complex 2

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Galvis, L. A., Holik, A. Z., Short, K. M., Pasquet, J., Lun, A. T. L., Blewitt, M. E., ... Labat, M-L. (2015). Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung. Development (Cambridge), 142(8), 1458-1469. https://doi.org/10.1242/dev.122077

Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung. / Galvis, Laura A.; Holik, Aliaksei Z.; Short, Kieran M.; Pasquet, Julie; Lun, Aaron T.L.; Blewitt, Marnie E.; Smyth, Ian M.; Ritchie, Matthew E.; Labat, Marie-Liesse.

In: Development (Cambridge), Vol. 142, No. 8, 01.01.2015, p. 1458-1469.

Research output: Contribution to journalArticle

Galvis, LA, Holik, AZ, Short, KM, Pasquet, J, Lun, ATL, Blewitt, ME, Smyth, IM, Ritchie, ME & Labat, M-L 2015, 'Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung', Development (Cambridge), vol. 142, no. 8, pp. 1458-1469. https://doi.org/10.1242/dev.122077
Galvis LA, Holik AZ, Short KM, Pasquet J, Lun ATL, Blewitt ME et al. Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung. Development (Cambridge). 2015 Jan 1;142(8):1458-1469. https://doi.org/10.1242/dev.122077
Galvis, Laura A. ; Holik, Aliaksei Z. ; Short, Kieran M. ; Pasquet, Julie ; Lun, Aaron T.L. ; Blewitt, Marnie E. ; Smyth, Ian M. ; Ritchie, Matthew E. ; Labat, Marie-Liesse. / Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung. In: Development (Cambridge). 2015 ; Vol. 142, No. 8. pp. 1458-1469.
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