Sex-Stratified Gene Regulatory Networks Reveal Female Key Driver Genes of Atherosclerosis Involved in Smooth Muscle Cell Phenotype Switching.
Sex-Stratified Gene Regulatory Networks Reveal Female Key Driver Genes of Atherosclerosis Involved in Smooth Muscle Cell Phenotype Switching.
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DOI：
10.1161/circulationaha.120.051231
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发表时间：
2021-02-16
期刊：
影响因子：
37.8
通讯作者：
den Ruijter HM
中科院分区：
文献类型：
--
作者：
Hartman RJG;Owsiany K;Ma L;Koplev S;Hao K;Slenders L;Civelek M;Mokry M;Kovacic JC;Pasterkamp G;Owens G;Björkegren JLM;den Ruijter HM
虽然冠状动脉疾病 (CAD) 中的性别差异已被广泛接受，女性比男性患上更稳定的动脉粥样硬化，但这种差异的潜在病理学仍然很大程度上未知。在 CAD 中，最近的综合系统生物学研究推断出基因调控网络 (GRN)。在这些 GRN 中，关键的驱动基因已显示出巨大的前景，但迄今为止在女性中尚未得到证实。在斯德哥尔摩-塔尔图动脉粥样硬化逆向网络工程任务 (STARNET) 研究中，我们生成了 160 名女性和年龄匹配男性的动脉粥样硬化动脉壁的性别特异性 GRN。我们将雌性 GRN 与人类动脉粥样硬化斑块的单细胞 RNA 测序数据以及野生型和 Klf4 敲除动脉粥样硬化 SMC 谱系追踪小鼠的晚期动脉粥样硬化病变的单细胞 RNA 测序数据整合在一起。通过比较性别特异性 GRN，我们观察到动脉粥样硬化组织内网络活动存在明显的性别差异。女性中更活跃的基因与间充质细胞和内皮细胞有关，而男性中更活跃的基因与免疫系统有关。通过对人类动脉粥样硬化斑块进行单细胞测序，我们确定在女性 CAD 中活跃的 GRN 的关键驱动因素主要存在于平滑肌细胞 (SMC) 中，并且在女性斑块 SMC 中表达较高。为了研究这些雌性 SMC 在动脉粥样硬化中关键驱动因素的功能，我们检查了来自野生型和 Klf4 敲除动脉粥样硬化 SMC 谱系追踪小鼠的晚期动脉粥样硬化病变的单细胞 RNA 测序。研究发现，女性关键驱动因素由表型调节的 SMC 表达，并受 Klf4 影响，表明动脉粥样硬化的性别差异涉及斑块 SMC 的表型转换。我们的系统方法为动脉粥样硬化性别差异背后的分子机制提供了新的见解。为了发现动脉粥样硬化的性别特异性治疗靶点，有必要在多组学数据集分析中更加重视性别分层方法。
While sex differences in coronary artery disease (CAD) are widely accepted with women developing more stable atherosclerosis than men, the underlying pathobiology of such differences remains largely unknown. In CAD, recent integrative systems biological studies have inferred gene regulatory networks (GRNs). Within these GRNs, key driver genes have shown great promises but have thus far been unidentified in females. We generated sex-specific GRNs of the atherosclerotic arterial wall in 160 females and age-matched males in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study. We integrated the female GRNs with single-cell RNA-sequencing data of the human atherosclerotic plaque and single-cell RNA-sequencing of advanced atherosclerotic lesions from wildtype and Klf4 knock-out atherosclerotic SMC lineage tracing mice. By comparing sex-specific GRNs, we observed clear sex differences in network activity within the atherosclerotic tissues. Genes more active in females were associated with mesenchymal cells and endothelial cells, whereas genes more active in males were associated with the immune system. We determined that key drivers of GRNs active in female CAD were predominantly found in smooth muscle cells (SMCs) by single-cell sequencing of the human atherosclerotic plaques, as well as higher expressed in female plaque SMCs. To study the functions of these female SMC key drivers in atherosclerosis, we examined single-cell RNA-sequencing of advanced atherosclerotic lesions from wildtype and Klf4 knock-out atherosclerotic SMC lineage tracing mice. The female key drivers were found to be expressed by phenotypically modulated SMCs and affected by Klf4, suggesting that sex differences in atherosclerosis involves phenotypic switching of plaque SMCs. Our systems approach provides novel insights into molecular mechanisms that underlie sex differences in atherosclerosis. To discover sex-specific therapeutic targets for atherosclerosis, an increased emphasis on sex-stratified approaches in the analysis of multi-omics datasets is warranted.