Histone Variant H2A.Z Is Required for the Maintenance of Smooth Muscle Cell Identity as Revealed by Single-Cell Transcriptomics
Histone Variant H2A.Z Is Required for the Maintenance of Smooth Muscle Cell Identity as Revealed by Single-Cell Transcriptomics
复制标题
单细胞转录组学揭示组蛋白变体 H2A.Z 是维持平滑肌细胞身份所必需的
DOI：
10.1161/circulationaha.117.033114
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发表时间：
2018-11-13
期刊：
影响因子：
37.8
通讯作者：
Wang, Li
中科院分区：
文献类型：
--
作者：
Yao, Fang;Yu, Peng;Wang, Li
背景：组蛋白变异体赋予染色质特定的结构，在发育和疾病中起重要作用。然而，很少有人知道他们在控制血管疾病的细胞身份的作用。研究方法：鉴于动脉粥样硬化病变中的细胞异质性，我们应用单细胞RNA测序分析患病的人类动脉，并确定组蛋白变体H2A. Z作为维持血管平滑肌细胞（VSMC）身份的关键组蛋白签名。结果：我们发现H2A. Z占据了VSMC标记基因附近的基因组区域，并且在去分化的VSMC中其占据率降低。从机制上讲，H2A.Z占据优先促进核小体周转，并促进SMAD3和MED1的募集，从而激活VSMC标志物基因表达。此外，与正常动脉中的那些相比，患病的人血管组织中的H2A. Z表达在mRNA和蛋白质水平上均显著降低。值得注意的是，H2A.Z的体内过表达挽救了损伤诱导的VSMC身份丧失和新生内膜形成。结论：总之，我们的数据介绍了动态占用组蛋白变体作为一种新的监管基础，有助于细胞命运的决定，并暗示H2A.Z作为一个潜在的干预节点血管疾病。
Background: Histone variants endow chromatin with specific structures, and play essential roles in development and diseases. However, little is known about their roles in controlling cell identity in vascular diseases. Methods: Given the cell heterogeneity in atherosclerotic lesions, we applied single-cell RNA-Sequencing to analyze diseased human arteries, and identified histone variant H2A.Z as a key histone signature to maintain vascular smooth muscle cell (VSMC) identity. Results: We show that H2A.Z occupies genomic regions near VSMC marker genes, and its occupancy is decreased in VSMCs undergoing dedifferentiation. Mechanistically, H2A.Z occupancy preferentially promotes nucleosome turnover, and facilitates the recruitment of SMAD3 and MED1, thereby activating VSMC marker gene expression. In addition, H2A.Z expression is dramatically reduced at both mRNA and protein levels in diseased human vascular tissues compared to those in normal arteries. Notably, in vivo overexpression of H2A.Z rescues injury-induced loss of VSMC identity and neointima formation. Conclusions: Together, our data introduce dynamic occupancy of a histone variant as a novel regulatory basis contributing to cell fate decisions, and imply H2A.Z as a potential intervention node for vascular diseases.