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bioRxiv · 10.1101/674127

Slug/Snail2 is involved in the repression of proliferation genes by TGF-β in bronchial epithelial progenitor cells and is deregulated in abnormal epithelium

Ben Brahim, C.·Courageux, C.·Jolly, A.·Ouine, B.·Cartier, A.·de la Grange, P.·de Koning, L.·Leroy, P.
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Abstract

Slug/Snail2 belongs to the Epithelial-Mesenchymal Transition (EMT)-inducing transcription factors involved in development and diseases. Slug is expressed in adult stem/progenitor cells of several epithelia, making it unique among these transcription factors. To investigate Slug role in human bronchial epithelium progenitors, we studied primary bronchial basal/progenitor cells in an air-liquid interface culture system that allows regenerating a bronchial epithelium. To identify Slug downstream genes we knocked down Slug in basal/progenitor cells from normal subjects and subjects with COPD, a respiratory disease presenting anomalies in the bronchial epithelium and high levels of TGF-{beta} in the lungs. We show that normal and COPD bronchial basal/progenitors, even when treated with TGF-{beta}, express both epithelial and mesenchymal markers, and that the epithelial marker E-cadherin is not a target of Slug and, moreover, positively correlates with Slug. We reveal that Slug downstream genes responding to both differentiation and TGF-{beta} are different in normal and COPD progenitors, with in particular a set of proliferation-related genes that are among the genes repressed downstream of Slug in normal but not COPD. In COPD progenitors at the onset of differentiation in presence of TGF-{beta}, we show that there is positive correlations between the effect of differentiation and TGF-{beta} on proliferation-related genes and on Slug protein, and that their expression levels are higher than in normal cells. As well, the expression of Smad3 and {beta}-Catenin, two molecules from TGF-{beta} signaling pathways, are higher in COPD progenitors, and our results indicate that proliferation-related genes and Slug protein are increased by different TGF-{beta}-induced mechanisms. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/674127v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@524a15org.highwire.dtl.DTLVardef@7dd1e5org.highwire.dtl.DTLVardef@5f3798org.highwire.dtl.DTLVardef@13ae179_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Ben Brahim, C., Courageux, C., Jolly, A., Ouine, B., Cartier, A., de la Grange, P., de Koning, L., Leroy, P.. 2019-06-17. Slug/Snail2 is involved in the repression of proliferation genes by TGF-β in bronchial epithelial progenitor cells and is deregulated in abnormal epithelium. https://doi.org/10.1101/674127

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