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

Coordinated expression of differentiation and innate pathways is essential for successful mucosal injury-repair. Previously, we discovered that the core SWI/SNF complex ATPase, SWI/SNF-related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4)/Brg1, maintains tumor protein 63 + basal progenitor cells in an epithelial-committed state. In response to viral injury, SMARCA4 complexes BRD4 to activate innate inflammation and promote mesenchymal transition/plasticity. To investigate how innate inflammation couples with plasticity, Cleavage Under Targets and Release Using Nuclease of BRD4 binding was applied to wild type and SMARCA4 knockdown (KD) in mock- or respiratory syncytial virus (RSV)-infected basal cells. In mock-infected cells, BRD4 binds 4017 high-confidence peaks within gene bodies controlling mesenchymal transition pathways. By contrast, RSV replication repositions 2339 BRD4 peaks to open chromatin regions upstream of the genes controlling inducible cytokine, cell adherence, and antiviral programs. Also, we note RSV redistributes BRD4 into super enhancers regulating immune response-associated long noncoding (lnc)RNAs. In SMARCA4 KD cells, BRD4 distribution is reduced on 739 peaks after RSV infection. The boundaries of nucleosome-free regions are reduced by SMARCA4 KD, suggesting its role in maintaining open chromatin of super enhancers. Specifically, SMARCA4-BRD4 enhancer controls lncRNAs important in interferon response factor 1 autoregulation. These data indicate how SWI/SNF ATPases couple BRD4 to lncRNA expression controlling cell state and intrinsic immunity in epithelial injury-repair.