The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci

Abstract

Rationale: Vascular beds have distinct susceptibility to atherosclerosis and aneurysm, yet the biological underpinnings of vascular bed specific disease risk are largely unknown. Vascular tissues have different developmental origins which may influence global chromatin accessibility. Understanding chromatin accessibility and gene expression profiles on single cell resolution is crucial to gain insight into vascular bed specific disease risk. Objective: We aim to understand, on single cell resolution, the global chromatin accessibility and gene expression profiles across distinct vascular beds in the healthy adult mouse to provide insight into the potential mechanisms of vascular bed specific disease risk. Methods and Results: We performed single cell chromatin accessibility (scATACseq) and gene expression profiling (scRNAseq) of healthy adult mouse vascular tissue from three vascular beds, 1) aortic root and ascending aorta, 2) brachiocephalic and carotid artery, and 3) descending thoracic aorta. By integrating datasets and comparing vascular beds within cell type, we identified thousands of differentially accessible chromatin peaks within smooth muscle cells, fibroblasts, and endothelial cells, demonstrating numerous enhancers to be vascular bed specific. We revealed an epigenetic memory of embryonic origin with differential chromatin accessibility of key developmental transcription factors such as Tbx20, Hand2, Gata4, and Hoxb family. Differentially accessible chromatin regions within cell type are also heavily weighted towards genes with known roles in mediating vascular disease risk. Furthermore, cell type specific transcription factor motif accessibility varies by vascular bed, all of which suggest epigenomic profiles as having specific roles in vascular bed specific disease risk. Conclusions: This work supports a paradigm that the epigenomic landscapes of vascular cells are cell type and vascular bed specific and that differentially accessible regions are heavily weighted towards disease risk genes. This work gives insight into vascular bed specific transcriptional and epigenetic programs and highlights the potential for vascular bed specific mechanisms of disease.