|
Status |
Public on Mar 28, 2023 |
Title |
The chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and in situ vascular fibrosis [CUT&RUN] |
Organism |
Mus musculus |
Experiment type |
Other
|
Summary |
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-β1 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-β1-induced phenotypic transition. Mechanistically, TGF-β1 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 |
To obtain differential binding analysis of Brg1-DNA interactions in the AdvSca1-SM genome of AdvSca1-SM cells maintained in the following experimental conditions for 72 hours: stem/baseline, 5ng/mL TGF-B, or 5ng/mL TGF-B + 50uM PFI-3.
|
|
|
Contributor(s) |
Jolly AJ, Lu S, Dubner AM, Strand KA, Mutryn MF, Pilotti-Riley A, Danis EP, Nemenoff RA, Moulton KS, Majesky MW, Weiser-Evans MC |
Citation(s) |
36976650 |
|
Submission date |
Aug 17, 2022 |
Last update date |
Mar 31, 2023 |
Contact name |
Mary C.M. Weiser-Evans |
E-mail(s) |
Mary.weiser@ucdenver.edu
|
Phone |
303-724-4846
|
Organization name |
University of Colorado Anschutz Medical Campus
|
Department |
Renal Diseases & Hypertension
|
Lab |
Dr. Mary C.M. Weiser-Evans
|
Street address |
12700 East 19th Avenue, C281
|
City |
Aurora |
State/province |
CO |
ZIP/Postal code |
80045 |
Country |
USA |
|
|
Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
Samples (3) |
|
This SubSeries is part of SuperSeries: |
GSE211423 |
The chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and in situ vascular fibrosis. |
|
Relations |
BioProject |
PRJNA870289 |