Unveiling the Genomic Organization at GWAS Loci at Risk for Non-Syndromic Mitral Valve Prolapse
Sergiy Kyryachenko1, Mengyao Yu1, Adrien Georges1, Russell Norris2, Nabila Bouatia-Naji1.
1INSERM UMR970, Paris Cardiovascular Research Center, Paris, France, 2Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
OBJECTIVE: In our recent genome-wide association study (GWAS), we described six associated risk loci for non-syndromic mitral valve prolapse (MVP), all located in intergenic and intronic regions. This study aims to examine the genomic context at the MVP-associated loci to provide clues on gene regulation and help identify causal genes.
METHODS: We performed an assay for transposase-accessible chromatin followed by high-throughput sequencing (ATAC-seq) to assess the chromatin state in dermal and cardiac fibroblasts. We performed Chromosome Conformation Capture experiments (3C) in cardiac fibroblasts to investigate long-range interactions at one specific locus on Chr17 intronic to SMG6.
RESULTS: ATAC-seq data revealed profiles of chromatin accessibility that were consistent overall between dermal and cardiac fibroblasts. We then combined our data with publicly available ChIP-seq datasets for enhancer and promoter marks to define regulatory regions enriched at associated loci. We decided to explore the intronic SMG6 locus since it is known as a risk locus for several cardiovascular traits, including MVP, and our previous functional studies, including zebrafish knockdown of 2 candidates, SMG6 and SGSM2, failed to support their role in valve development. We found an abundance of potential regulatory regions at this locus. Using 3C experiments in cardiac fibroblasts, we demonstrate that the top associated variant physically interacts with unexplored proximal and distal genes with relevant candidate function.
CONCLUSIONS: Our study provides the first chromatin accessibility map in cardiac fibroblasts and points at potential regulatory elements that co-localize with MVP-associated loci. We provide new functional elements about the potential molecular mechanisms of regulation on Chr17, a highly replicated locus in CVD related GWAS. Our current efforts are focused on testing the regulatory capacities of the associated sequences in vitro and performing 4C experiments in more relevant cell type to mitral valve biology, e.g. VECs and VICs at the remaining associated loci.
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