Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk.

Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies (GWAS) have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements (CREs). Here, we applied single-nucleus ATAC-seq to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell type-specific elements, transcription factors, and prioritized functional CAD risk variants. . We identified elements in smooth muscle cell (SMC) transition states (e.g. fibromyocytes) and functional variants predicted to alter SMC and macrophage-specific regulation of MRAS (3q22) and LIPA (10q23), respectively. We further nominated key driver transcription factors such as PRDM16 and TBX2. Together, this single nucleus atlas provides a critical step towards interpreting regulatory mechanisms across the continuum of CAD risk.

冠状动脉疾病（CAD）是一种复杂的炎症性疾病，涉及多种细胞类型的遗传影响。全基因组关联研究（GWAS）已经确定了200多个与CAD相关的基因位点，其中大多数风险变异存在于影响顺式调控元件（CREs）的非编码DNA序列中。在此，我们应用单核ATAC - seq技术对41例不同CAD阶段患者的冠状动脉节段中的28316个细胞核进行了分析，揭示了14个不同的细胞簇。我们绘制了所有细胞中约32万个可及位点，确定了细胞类型特异性元件、转录因子，并对功能性CAD风险变异进行了优先级排序。我们确定了平滑肌细胞（SMC）过渡状态（例如纤维肌细胞）中的元件，以及预计分别改变SMC和巨噬细胞对MRAS（3q22）和LIPA（10q23）特异性调控的功能性变异。我们还提名了关键驱动转录因子，如PRDM16和TBX2。总之，这个单核图谱为解释CAD风险连续过程中的调控机制迈出了关键的一步。