Genes coding for transcription factors involved in stem cell maintenance are repressed by TGF-β and downstream of Slug/Snail2 in COPD bronchial epithelial progenitors,Molecular Biology Reports

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Genes coding for transcription factors involved in stem cell maintenance are repressed by TGF-β and downstream of Slug/Snail2 in COPD bronchial epithelial progenitors
Molecular Biology Reports ( IF 2.6 ) Pub Date : 2021-08-26 , DOI: 10.1007/s11033-021-06664-8
Pierre de la Grange ₁ , Ariane Jolly ₁ , Charlotte Courageux _{2,

3} , Chamseddine Ben Brahim _{2,

3} , Pascale Leroy _{2,

3}

Affiliation

Background

Basal stem/progenitor cells of airway epithelium from chronic obstructive pulmonary disease (COPD) patients have a decrease in differentiation and self-renewal potential. Our study aimed at identifying deregulations in the genetic program of these cells that could account for their exhaustion, focusing on genes downstream of the epithelial–mesenchymal transition-inducing transcription factor Slug/Snail2 and responding to transforming growth factor (TGF)-β. TGF-β is at higher levels in COPD patient lungs, plays a role in stem/progenitor cell fate and regulates the expression of Slug/Snail2 that is highly expressed in airway basal stem/progenitors.

Methods and results

We reanalyzed a gene expression dataset that we generated from COPD and normal primary bronchial basal progenitor cells knocked down for Slug/Snail2 gene. Among the genes that we identified to be repressed downstream of Slug/Snail2 in COPD, we selected those responding to differentiation and TGF-β. The large majority of these genes are upregulated with differentiation but repressed by TGF-β. Pathway and ontology enrichment analysis revealed a set of genes coding for transcription factors involved in stem cell maintenance that are repressed downstream of Slug/Snail2 and by TGF-β in COPD but not normal basal progenitor cells. We also reveal a link between Slug/Snail2 expression and the repressive effect of TGF-β on these stem cell maintenance genes.

Conclusion

Our work brings a new insight and molecular perspective to the exhaustion of basal stem/progenitor cells observed in the airway epithelium of COPD patients, revealing that stem cell maintenance genes are repressed in these cells, with TGF-β and Slug/Snail2 being involved in this deregulation.

Graphic abstract

中文翻译：

编码参与干细胞维持的转录因子的基因被 TGF-β 和 COPD 支气管上皮祖细胞中 Slug/Snail2 的下游抑制

背景

来自慢性阻塞性肺病 (COPD) 患者的气道上皮基底干/祖细胞的分化和自我更新潜力降低。我们的研究旨在确定这些细胞遗传程序中可能导致其衰竭的失调，重点关注上皮-间质转化诱导转录因子 Slug/Snail2 下游的基因以及对转化生长因子 (TGF)-β 的反应。TGF-β 在 COPD 患者的肺中处于较高水平，在干细胞/祖细胞命运中发挥作用并调节在气道基底干/祖细胞中高度表达的 Slug/Snail2 的表达。

方法和结果

我们重新分析了从 COPD 和正常初级支气管基底祖细胞生成的基因表达数据集，这些细胞因 Slug/Snail2 基因而被敲除。在我们确定在 COPD 中 Slug/Snail2 下游被抑制的基因中，我们选择了那些对分化和 TGF-β 有反应的基因。这些基因中的大多数随着分化而上调，但被 TGF-β 抑制。通路和本体富集分析揭示了一组编码参与干细胞维持的转录因子的基因，这些转录因子在 Slug/Snail2 的下游和 COPD 中的 TGF-β 而不是正常的基底祖细胞中被抑制。我们还揭示了 Slug/Snail2 表达与 TGF-β 对这些干细胞维持基因的抑制作用之间的联系。