SMARCA4 regulates inducible BRD4 genomic redistribution coupling intrinsic immunity and plasticity in epithelial injury-repair.

Summary

Using CUT&RUN in RSV-infected basal epithelial cells, the authors show that SMARCA4 orchestrates BRD4 redistribution from mesenchymal gene bodies to open chromatin and super-enhancers that regulate cytokines, adhesion, antiviral programs, and immune lncRNAs. SMARCA4 knockdown reduces BRD4 occupancy and nucleosome-free region boundaries, implicating SWI/SNF ATPases in maintaining enhancer openness and coupling lncRNA expression to intrinsic antiviral immunity and epithelial plasticity.

Key Findings

• RSV replication repositions 2339 BRD4 peaks to open chromatin upstream of inducible cytokine, adhesion, and antiviral genes.
• RSV redistributes BRD4 into super-enhancers that regulate immune response–associated lncRNAs; SMARCA4 knockdown reduces BRD4 occupancy on 739 peaks.
• SMARCA4 maintains nucleosome-free region boundaries at super-enhancers and controls lncRNAs important for IRF1 autoregulation, coupling intrinsic immunity with epithelial plasticity.

Clinical Implications

While preclinical, targeting SMARCA4-BRD4 enhancer dynamics or downstream immune lncRNAs could modulate epithelial repair and antiviral responses in severe RSV infection and related airway injury.

Limitations

• Findings are primarily from in vitro basal epithelial models; in vivo validation is limited.
• Functional rescue and therapeutic modulation of specific lncRNAs or enhancers were not tested.

Future Directions

Validate enhancer–lncRNA–immune circuitry in vivo, define druggable nodes (e.g., BRD4/SMARCA4 interfaces), and test whether modulating these pathways improves outcomes in RSV or other epithelial injury.