Poster #51 - Sungryong Oh

Interpreting congenital heart disorders by comprehensive analysis of cell type-specific gene regulatory program in the developing human heart.

Sungryong Oh1, Kevin Child2, Pooja Sonawane2, and Justin Cotney1 1. Dep. of Plastic Surgery, Children's Hospital of Philadelphia, Philadelphia 19104, USA 2. Dep. of Genetics and Genome Science, University of Connecticut Health Center, Farmington 06030, USA

Congenital heart diseases (CHD) are among the most common defects found in newborns. However, around 50% of non-syndromic CHD cases remain unexplained neither by genetic mutations nor by environmental factors, with highly variable symptoms and severity. Several reports suggest that defects in non-coding regions could be at fault in these unexplained cases, but still unclear how these abnormalities result in CHDs. To address this gap, we focused on uncovering the gene regulatory dynamics of developing human heart at the single-cell level in overall prenatal period. We performed joint profiling of gene expression and chromatin accessibility in single nuclei (snMultiome) from early 4-6 weeks heart tissues. By integrating with other single-cell RNA sequencing of fetal hearts, we identified 15 distinct clusters of 86,549 cells based on transcriptomes. This includes previously unknown small cell types enriched in early developing heart cells, as well as most of cell types found in the fetal heart. This encompasses most of the structural milestones of heart development and when many critical cell types are specified. We also profiled open chromatin accessibility in 54,644 developing human heart and get 393,331 significant regions which are opened in cell-type and developmental stage-specific manner. By integrating these two modalities, we clarify progenitor cell types involved into a certain cell-types, including cardiomyoctes and epicardial cell types. By intersecting cell type specificity with GWAS studies, we could observe that that distinct early heart subtypes are correlated to distinct CHD subtypes as well as different cardiac features in developing heart. This our gene regulatory program in cardiac relevant cell types allowed us to identify highly accessible genomic regions linked to risk factors for CHDs in cell type and stage specific manner. Overall, this approach provides a comprehensive understanding of human heart organogenesis and offers valuable genetic insights into unexplained CHD cases.