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- W4312728535 abstract "Background: Vascular smooth muscle cell (SMC) phenotype modulation produces a mixed proteolytic/collagen synthetic state in Marfan syndrome (MFS) aortic root aneurysm. While the transcriptomic changes associated with this process are established, upstream regulators governing this plasticity are poorly characterized. Methods/Results: We performed concurrent single-cell RNA sequencing (scRNAseq) and assay for transposase-accessible chromatin using sequencing (scATACseq) on aortic root aneurysm tissue from adult Fbn1 C1041G/+ (MFS) mice and littermate controls. MFS/control scRNAseq data analysis identified four SMC subtypes including MFS-specific ‘modulated’ cells (modSMCs) which enriched for extracellular matrix organization and collagen synthesis pathway activation. These SMC clusters were projected onto the MFS/control scATAC dataset via integrative label transfer to study dynamic chromatin accessibility during SMC phenotype modulation. We compared DNA accessibility in modSMCs versus mature SMCs, finding 336 enriched and 29 suppressed peaks, suggesting increased open chromatin during modulation. Using chromVAR, we identified 242 enriched transcription factor motifs overrepresented in modSMCs. Motifs representing central but nonspecific transcription factor families including numerous AP-1 (FOS/JUN/ATF) heterodimers and TEAD family members showed highest enrichment, while enriched TWIST1, HAND2, and SMAD2:SMAD3:SMAD4 complex motifs suggested more specific functions. To functionally validate these findings, we examined TWIST1 as a potential regulator of SMC modulation in vitro via lentiviral overexpression in MFS patient-derived aortic SMCs.In SMCs with forced TWIST1 overexpression, we found heightened promoter region DNA accessibility (via bulk ATACseq) and increased mRNA expression (via RT-PCR) for specific modSMC markers (e.g., COL1A1 and LUM confirming TWIST1 promotes collagen synthesis. Conclusions: Integrated single-cell transcriptomic/epigenomic analysis permits identification of critical upstream regulatory signals promoting disease-specific cell phenotype changes. TWIST1 is a potential driver of SMC modulation and a target for therapeutic agent design in MFS aortic aneurysm." @default.
- W4312728535 created "2023-01-05" @default.
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- W4312728535 date "2022-05-01" @default.
- W4312728535 modified "2023-09-30" @default.
- W4312728535 title "Abstract 360: Epigenomic Changes Govern Smooth Muscle Cell Phenotype Shift In Marfan Syndrome Aortic Root Aneurysm" @default.
- W4312728535 doi "https://doi.org/10.1161/atvb.42.suppl_1.360" @default.
- W4312728535 hasPublicationYear "2022" @default.
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