Single-Cell Analysis Identify Transcription Factor BACH1 as a Master Regulator Gene in Vascular Cells During Aging.
Single-Cell Analysis Identify Transcription Factor BACH1 as a Master Regulator Gene in Vascular Cells During Aging.
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DOI：
10.3389/fcell.2021.786496
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发表时间：
2021
影响因子：
5.5
通讯作者：
Meng D
中科院分区：
文献类型：
--
作者：
Ge F;Pan Q;Qin Y;Jia M;Ruan C;Wei X;Jing Q;Zhi X;Wang X;Jiang L;Osto E;Guo J;Meng D
血管老化是心血管和脑血管疾病的潜在驱动力。血管衰老的特征是细胞和功能的变化，但其分子机制和细胞异质性知之甚少。本研究旨在1）探索猴和小鼠衰老心脏血管的细胞和分子特性; 2）阐明转录因子BACH 1在内皮细胞（EC）衰老调节中的作用及其机制。在这里，我们分析了已发表的来自猴子冠状动脉和主动脉弓以及小鼠心脏的单细胞RNA测序（scRNA-seq）数据。结果显示，衰老的猴冠状动脉内皮细胞和小鼠心肌毛细血管内皮细胞中YAP 1、胰岛素受体和VEGF受体2的基因表达均下调，与增殖相关的心肌毛细血管内皮细胞数量明显减少。在猴和小鼠的老化血管中观察到EC和免疫细胞的相互作用增加。基因调控网络分析确定BACH 1是猴冠状动脉和主动脉EC以及小鼠心脏EC中衰老相关基因的主要调控因子。BACH 1在衰老小鼠心脏EC和动脉中的表达上调。BACH 1可加重氧化应激下内皮细胞的衰老。从机制上讲，BACH 1占据开放染色质区域并与CDKN 1A（编码P21）基因增强子结合，激活其在衰老的人脐静脉内皮细胞（HUVEC）中的转录。因此，这些发现表明BACH 1在内皮细胞衰老和血管老化中起重要作用。
Vascular aging is a potent driver of cardiovascular and cerebrovascular diseases. Vascular aging features cellular and functional changes, while its molecular mechanisms and the cell heterogeneity are poorly understood. This study aims to 1) explore the cellular and molecular properties of aged cardiac vasculature in monkey and mouse and 2) demonstrate the role of transcription factor BACH1 in the regulation of endothelial cell (EC) senescence and its mechanisms. Here we analyzed published single-cell RNA sequencing (scRNA-seq) data from monkey coronary arteries and aortic arches and mouse hearts. We revealed that the gene expression of YAP1, insulin receptor, and VEGF receptor 2 was downregulated in both aged ECs of coronary arteries’ of monkey and aged cardiac capillary ECs of mouse, and proliferation-related cardiac capillary ECs were significantly decreased in aged mouse. Increased interaction of ECs and immunocytes was observed in aged vasculature of both monkey and mouse. Gene regulatory network analysis identified BACH1 as a master regulator of aging-related genes in both coronary and aorta ECs of monkey and cardiac ECs of mouse. The expression of BACH1 was upregulated in aged cardiac ECs and aortas of mouse. BACH1 aggravated endothelial cell senescence under oxidative stress. Mechanistically, BACH1 occupied at regions of open chromatin and bound to CDKN1A (encoding for P21) gene enhancers, activating its transcription in senescent human umbilical vein endothelial cells (HUVECs). Thus, these findings demonstrate that BACH1 plays an important role in endothelial cell senescence and vascular aging.
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