ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis.
ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis.
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DOI：
10.1161/circulationaha.121.057789
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发表时间：
2022-02-08
期刊：
影响因子：
37.8
通讯作者：
Quertermous T
中科院分区：
文献类型：
--
作者：
Cheng P;Wirka RC;Shoa Clarke L;Zhao Q;Kundu R;Nguyen T;Nair S;Sharma D;Kim HJ;Shi H;Assimes T;Brian Kim J;Kundaje A;Quertermous T
在动脉粥样硬化过程中，平滑肌细胞(SMC)转变为许多不同的表型，包括那些类似成纤维细胞和软骨细胞的细胞，并构成动脉粥样硬化斑块中的大多数细胞。为了更好地了解介导这些细胞状态变化的表观遗传和转录机制，以及它们如何与冠状动脉疾病(CAD)的风险相关，我们研究了全基因组相关基因座上转录因子(TF)的因果关系和功能。我们利用CRISPR-Cas 9基因组和表观基因组编辑技术，在2q22.3定位了一个复杂的CADGwas信号的致病基因和细胞(S)。随后，采用单细胞表观遗传学和转录图谱分析方法，在小鼠模型和人冠状动脉平滑肌细胞中研究了该CAD危险基因发挥作用的细胞和分子机制。CRISPR-Cas 9基因组和表观基因组编辑表明，2q22.3的基因组区域内复杂的CAD遗传信号存在于ZEB2的平滑肌远程增强子中，ZEB2是一种在发育和癌症的上皮间充质转化(EMT)背景下广泛研究的转铁蛋白。ZEB2通过染色质重塑来调节SMC的表型转换，这种重塑排除了可及性并干扰了Notch和转化生长因子β信号转导，从而改变了SMC转换的表观遗传轨迹。SMC特异性缺失ZEB2导致过渡的SMC不能关闭收缩程序并呈现成纤维细胞样表型，但加速了软骨肌细胞的形成，反映了人类冠状动脉高危动脉粥样硬化斑块的特征。这些研究证实ZEB2是一种新的CAD GWA型基因，它通过直接作用于表观基因组影响斑块易损性的特征，为靶向血管疾病提供了一种新的治疗方法。
Smooth muscle cells (SMC) transition into a number of different phenotypes during atherosclerosis, including those that resemble fibroblasts and chondrocytes, and make up the majority of cells in the atherosclerotic plaque. To better understand the epigenetic and transcriptional mechanisms that mediate these cell state changes, and how they relate to risk for coronary artery disease (CAD), we have investigated the causality and function of transcription factors (TFs) at genome wide associated loci. We employed CRISPR-Cas 9 genome and epigenome editing to identify the causal gene and cell(s) for a complex CAD GWAS signal at 2q22.3. Subsequently, single-cell epigenetic and transcriptomic profiling in murine models and human coronary artery smooth muscle cells were employed to understand the cellular and molecular mechanism by which this CAD risk gene exerts its function. CRISPR-Cas 9 genome and epigenome editing showed that the complex CAD genetic signals within a genomic region at 2q22.3 lie within smooth muscle long-distance enhancers for ZEB2, a TF extensively studied in the context of epithelial mesenchymal transition (EMT) in development and cancer. ZEB2 regulates SMC phenotypic transition through chromatin remodeling that obviates accessibility and disrupts both Notch and TGFβ signaling, thus altering the epigenetic trajectory of SMC transitions. SMC specific loss of ZEB2 resulted in an inability of transitioning SMCs to turn off contractile programing and take on a fibroblast-like phenotype, but accelerated the formation of chondromyocytes, mirroring features of high-risk atherosclerotic plaques in human coronary arteries. These studies identify ZEB2 as a new CAD GWAS gene that affects features of plaque vulnerability through direct effects on the epigenome, providing a new thereapeutic approach to target vascular disease.