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SMARCA4 regulates BRD4 nuclear distribution in cellular plasticity

ABSTRACT: Inducible cell stress programs in basal epithelial cells shape repair and host defense pathways in mucosal surfaces. Previously, we discovered that expression of the core SWI/SNF complex ATPase, SMARCA4/Brg1, is required for genomic organization supporting a fully differentiated epithelial state, regulating cellular plasticity, paracrine mesenchymal signaling and anti-viral response. Here, we observe that SMARCA4 expression is intrinsically engaged with IFN response genes and dynamically engages the atypical histone acetyltransferase, BRD4, upon RSV infection, an association required for intrinsic immunity. To investigate the mechanisms how the SMARCA4 BRD4 complex functions in intrinsic immunity, we performed Cleavage Under Targets and Release Using Nuclease (CUT&RUN) of BRD4 binding in wild type (WT) and SMARCA4 knockdown (KD) small airway epithelial cells in mock- or RSV-infected states. In mock-infected cells, 4,017 high confidence BRD4 peaks are identified that localize to the gene bodies controlling motility programs. By contrast, RSV replication repositions BRD4 to 2,339 regions, upstream of transcription start sites in genes controlling inducible cytokine, cell adherence and anti-viral programs. RSV redistributes BRD4 into super enhancers regulating immune response-associated long noncoding RNAs. BRD4 binding is not affected by SMARCA4 KD in mock-infected cells, but BRD4 recruitment is reduced on 739 peaks after RSV infection, including superenhancers. These data extend the complex interrelationship between the SWI/SNF ATPases and that of the BRD4 bromodomain epithelial progenitors linking cell state and innate immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273399 | GEO | 2024/08/30

REPOSITORIES: GEO

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