UC San Diego

Due to ethical considerations and practical limitations, there is a dearth of datasets that enable the characterization of early developmental processes. Large biorepositories of induced pluripotent stem cells (iPSCs) and derived tissues offer an opportunity to investigate the underexplored interval of early development. Here, we generate and analyze multiomic data from iPSCs and derived cardiovascular progenitor cells (CVPCs), and pancreatic progenitor cells (PPCs) from the iPSC ‘Omics Resource (iPSCORE) to characterize regulatory networks and variation that is active during early development.First, we analyzed 213 RNA-seq and 150 ATAC-seq samples generated from (iPSCs) reprogrammed from hundreds of iPSCORE individuals. We demonstrate that there is a high degree of pluripotent cell state variability across iPSC lines reprogrammed from different individuals. We identified 13 gene networks and 13 ATAC-seq peaks regulatory networks that are active in the primed and formative pluripotent cell states. Further, we identified independent formative-associated regulatory networks that are mediated by distinct transcription factors, suggesting that the regulation of pluripotency is more complex than previously known. Second, we conducted multiomic QTL analyses on RNA-seq, ATAC-seq, and H3K27ac ChIP-seq generated from three iPSCORE tissues including iPSCs, and derived cardiovascular progenitor cells (CVPCs) and pancreatic progenitor cells (PPCs). For each tissue, we integrated thousands of QTLs affecting gene expression (eQTLs), ATAC-seq chromatin accessibility (caQTLs), and H3K27ac ChIP-seq histone acetylation (haQTLs). We found that QTLs are often complex and regulate multiple elements (i.e. genes and/or peaks). Further, we show that the inclusion of chromatin QTLs (caQTLs and haQTLs) could explain ~2-fold more GWAS loci than eQTLs alone. Third, we performed multiomic modelling of immune cell-free cardiac inflammation by treating four CVPCs with pro-inflammatory cytokine, interferon gamma (IFNg). We observed the upregulation of hundreds of immune-related genes and an expansion of the cardiac endothelial cell population in response to IFNg treatment. We also show that IFN stimulates substantial chromatin remodeling and upregulates accessibility of ATAC-seq peaks are active in immune cell types. Taken together, we conducted several independent studies that demonstrated the utility of large biorepositories of iPSCs and derived tissues the characterize regulatory networks and variation in early developmental tissues.