Liu Yong, Pandey Rajan, Qiu Qiongzi, Liu Pengyuan, Xue Hong, Wang Jingli, Therani Bhavika, Ying Rong, Usa Kristie, Grzybowski Michael, Yang Chun, Mishra Manoj K, Greene Andrew S, Cowley Allen W, Rao Sridhar, Geurts Aron M, Widlansky Michael E, Liang Mingyu
Department of Physiology, University of Arizona College of Medicine - Tucson, Tucson, AZ, USA.
Molecular Systems Medicine Initiative, University of Arizona Health Sciences, Tucson, AZ, USA.
bioRxiv. 2024 Oct 14:2024.10.09.617511. doi: 10.1101/2024.10.09.617511.
Arterioles are small blood vessels located just upstream of capillaries in nearly all tissues. The constriction and dilation of arterioles regulate tissue perfusion and are primary determinants of systemic blood pressure (BP). Abnormalities in arterioles are central to the development of major diseases such as hypertension, stroke, and microvascular complications of diabetes. Despite the broad and essential role of arterioles in physiology and disease, current knowledge of the functional genomics of arterioles is largely absent, partly because it is challenging to obtain and analyze human arteriole samples. Here, we report extensive maps of chromatin interactions, single-cell expression, and other molecular features in human arterioles and uncover new mechanisms linking human genetic variants to gene expression in vascular cells and the development of hypertension. Compared to large arteries, arterioles exhibited a higher proportion of pericytes which were strongly associated with BP traits. BP-associated single nucleotide polymorphisms (SNPs) were enriched in chromatin interaction regions in arterioles, particularly through enhancer SNP-promoter interactions, which were further linked to gene expression specificity across tissue components and cell types. Using genomic editing in animal models and human induced pluripotent stem cells, we discovered novel mechanisms linking BP-associated noncoding SNP rs1882961 to gene expression through long-range chromatin contacts and revealed remarkable effects of a 4-bp noncoding genomic segment on hypertension in vivo. We anticipate that our rich data and findings will advance the study of the numerous diseases involving arterioles. Moreover, our approach of integrating chromatin interaction mapping in trait-relevant tissues with SNP analysis and in vivo and in vitro genome editing can be applied broadly to bridge the critical gap between genetic discoveries and physiological understanding.
小动脉是几乎所有组织中位于毛细血管上游的小血管。小动脉的收缩和舒张调节组织灌注，是全身血压（BP）的主要决定因素。小动脉异常是高血压、中风和糖尿病微血管并发症等主要疾病发生发展的核心。尽管小动脉在生理学和疾病中具有广泛而重要的作用，但目前对小动脉功能基因组学的了解却非常有限，部分原因是获取和分析人类小动脉样本具有挑战性。在此，我们报告了人类小动脉中染色质相互作用、单细胞表达及其他分子特征的详细图谱，并揭示了将人类遗传变异与血管细胞中的基因表达以及高血压发展相联系的新机制。与大动脉相比，小动脉中周细胞的比例更高，且周细胞与血压特征密切相关。与血压相关的单核苷酸多态性（SNP）在小动脉的染色质相互作用区域富集，特别是通过增强子SNP-启动子相互作用，这进一步与跨组织成分和细胞类型的基因表达特异性相关联。利用动物模型和人类诱导多能干细胞中的基因组编辑技术，我们发现了通过长程染色质接触将与血压相关的非编码SNP rs1882961与基因表达相联系的新机制，并揭示了一个4碱基对的非编码基因组片段在体内对高血压的显著影响。我们预计，我们丰富的数据和发现将推动对涉及小动脉的众多疾病的研究。此外，我们将性状相关组织中的染色质相互作用图谱与SNP分析以及体内和体外基因组编辑相结合的方法可广泛应用，以弥合遗传发现与生理理解之间的关键差距。
