Aortic Disease-Associated SNPs Lead to Epigenetic Regulation Alterations That Increase Susceptibility to Aortic Aneurysm and Dissection - Project Summary Thoracic aortic aneurysms and dissections (TAAD) are life-threatening conditions for which therapeutic options are limited. While genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with sporadic TAAD, the molecular mechanisms through which these SNPs contribute to disease development remain unclear. The long-term objective of this project is to elucidate the role of TAAD-associated SNPs in sporadic TAAD pathogenesis, with a focus on their epigenetic and regulatory functions in aortic cells. Recent research has shown that altered expression of extracellular matrix (ECM) and inflammatory genes, and related epigenetic changes play critical roles in the progression of aortic disease. Integrating GWAS data with single-cell chromatin accessibility (scATAC-seq) data from human aortic tissues has revealed that many TAAD-associated SNPs are located within accessible chromatin regions of aortic cells, suggesting that these SNPs influence regulatory elements activity. This project tests the hypothesis that the risk alleles of TAAD-associated SNPs alter the binding affinities of transcription factors (TFs), reshaping the local epigenetic landscape and driving target gene dysregulation. The proposed research will systematically investigate the epigenetic mechanisms by which sporadic TAAD-associated SNPs influence gene regulation. The first aim is to identify the functional cell types where these SNPs exert their effects by integrating GWAS data with scATAC-seq data to determine the cell types in which disease-associated SNPs are located within accessible chromatin regions. The second aim focuses on exploring the epigenetic modifications and TF binding at SNP-containing chromatin regions using integrative analyses of GWAS and CutRun-seq data, targeting key histone modifications and TFs. The third aim will conduct allele-specific analyses by combining whole-genome sequencing, scATAC-seq, and scRNA-seq data to determine the direct target genes of SNPs in specific aortic cells. By uncovering the functional and regulatory mechanisms of TAAD-associated SNPs, this study will provide critical insights into the genetic and epigenetic basis of aortic disease, potentially leading to new therapeutic strategies.
