Single-Cell RNA-Seq Analysis Reveals Lung Epithelial Cell Type-Specific Responses to HDM and Regulation by Tet1

Area of Science:

• Immunology
• Genomics
• Cell Biology

Background:

• House dust mite (HDM) exposure triggers allergic lung inflammation.
• Tet1 (Ten-eleven translocation 1) is known to protect against HDM-induced lung inflammation.
• The specific role of Tet1 in distinct lung epithelial cell types during inflammation requires further investigation.

Purpose of the Study:

• To investigate the function of Tet1 in individual lung epithelial cell types during HDM-induced inflammation.
• To analyze transcriptomic changes in response to HDM challenge and Tet1 deficiency.
• To identify cell type-specific responses within the lung epithelium.

Main Methods:

• Established a mouse model of HDM-induced lung inflammation using Tet1 knockout and wild-type mice.
• Utilized single-cell RNA sequencing (scRNA-seq) to analyze EpCAM+ lung epithelial cells.
• Performed bulk and cell type-specific transcriptomic analyses and transcription factor (TF) activity analysis.

Main Results:

• Identified eight EpCAM+ lung epithelial cell types, with AT2 cells being the most abundant.
• HDM challenge altered epithelial cell type proportions and induced cell type-specific transcriptomic changes.
• Tet1 deficiency resulted in altered expression of genes involved in inflammation, detoxification, oxidative stress, and tissue repair, alongside changes in TF activity.

Conclusions:

• Lung epithelial cells exhibit distinct and shared transcriptomic profiles during allergic lung inflammation.
• Tet1 deletion impacts transcriptomic networks across various lung epithelial cells, potentially promoting allergen-induced inflammation.
• HDM may drive differentiation of AP and BAS cells into AT2 cells, irrespective of Tet1 presence.