Abstract Body: Most SNPs associated with blood pressure (BP) are located in noncoding regions of the human genome, where they may regulate gene expression in BP-relevant cell types. However, the mechanisms by which these SNPs influence BP regulation are unclear. To address this, we developed comprehensive epigenomic landscapes in human induced pluripotent stem cell (iPSC)-derived endothelial cells (iECs) and vascular smooth muscle cells (iVSMCs), incorporating DNA methylation analysis (RRBS), transcriptome analysis (RNA-seq), chromatin state profiling (ATAC-seq), and chromatin interaction mapping (Micro-C).

We identified 5301, 8916, and 6046 chromatin loops in iECs and 5329, 7598, and 5228 loops in iVSMCs at 4, 8, and 16 kb resolutions (FDR < 0.05) respectively based on the Micro-C analysis. Remarkably, 82.4% and 83.8% of these chromatin contact regions in iECs and iVSMCs, respectively, harbored at least one known regulatory element such as an enhancer, promoter, or transcription factor binding site. Notably, 109 and 119 BP-associated SNPs were found within the chromatin contact regions of iECs and iVSMCs, respectively.

We further investigated chromatin contact regions that involved interactions of regulatory elements. In both iECs and iVSMCs, lower methylation levels were observed in chromatin contact regions involving promoter-promoter (PP) and enhancer-promoter (EP) interactions, compared to enhancer-enhancer (EE), enhancer-transcription factor binding site (ET), and promoter-transcription factor binding site (PT) interactions. Additionally, greater chromatin accessibility was observed in chromatin contact regions involving PP and EP interactions. BP-associated SNPs were significantly enriched in chromatin contact regions involving PP and EP interactions. Moreover, genes proximal to chromatin contact regions involving PP or EP interactions exhibited higher expression than those near EE or other regulatory element interactions.

These findings offer new insights into how chromatin interactions between regulatory elements define transcriptional states in human endothelial and vascular smooth muscle cells, providing a novel basis for understanding the genetic regulation of BP.