GSE211421
The chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and in situ vascular fibrosis [RNA-seq]
Smooth muscle-derived Sca1+ adventitial progenitor cells are tissue resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and matrix tissue. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the differentiation trajectory of AdvSca1-SM cells to myofibroblasts are unclear. Here we show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein was upregulated in AdvSca1-SM cells in vivo after acute vascular injury and pharmacological inhibition of the Brg1 bromodomain by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-ß1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness-related genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; Brg1 inhibition blocked TGF-ß1-induced phenotypic transition. Mechanistically, TGF-ß1 promoted redistribution of Brg1 from distal regulatory sequences of stemness-related genes and recruitment of Brg1 to promoters of myofibroblast-related genes. This recruitment of Brg1 to myofibroblast genes was blocked in the presence of PFI-3. These data shed insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating AdvSca1-SM phenotype will provide important anti-fibrotic clinical benefit. Overall design: Global, unbiased differential gene expression analysis of RNA-seq data for AdvSca1-SM cells in the following experimental conditions for 72 hours: stem/baseline, 5ng/mL TGF-B, or 5ng/mL TGF-B + 50uM PFI-3.