IRF1 mediates airway epithelial innate memory through priming BRD4- EP300 activity

Area of Science:

• Immunology
• Cell Biology
• Epigenetics

Background:

• Airway epithelial cells are repeatedly exposed to RNA viruses.
• Innate immune response (IIR) activation leads to antiviral defenses and repair.
• The existence of innate memory in airway cells is unknown.

Purpose of the Study:

• To establish a model of innate memory in human small airway basal epithelial cells (hSAECs).
• To investigate the mechanisms of Interferon Regulatory Factor 1 (IRF1)-dependent gene remodeling in trained hSAECs.
• To explore the role of the BRD4 chromatin remodeling complex (CRC) in innate memory.

Main Methods:

• Repetitive Toll-like receptor 3 (TLR3) pathway activation to "train" hSAECs.
• CRISPR/Cas9 knockdown, ChIP, Co-IP, and selective BRD4 CRC inhibitors.
• Analysis of gene expression, cell morphology, and chromatin modifications (H3K27ac).

Main Results:

• "Training" increased basal IIR gene expression, reducing Respiratory Syncytial Virus (RSV) replication.
• Trained hSAECs exhibited epithelial mesenchymal plasticity (EMP) with altered cell shape and mesenchymal gene expression.
• IRF1 was essential for innate memory; it coupled with the BRD4-EP300 CRC, enhancing EP300 recruitment and H3K27ac at IIR gene promoters.

Conclusions:

• hSAECs acquire innate memory via IRF1-BRD4-EP300 CRC interactions, activating IIR and cell-state transition genes.
• Innate training results from dynamic BRD4 CRC interactions, enhancing EP300 recruitment and priming transcriptional responsiveness.