Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
Functional Gene Control Group, MRC Laboratory of Medical Sciences, London, UK.
Nat Cardiovasc Res. 2024 Jun;3(6):714-733. doi: 10.1038/s44161-024-00474-4. Epub 2024 Jun 6.
Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1-CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets.
血管平滑肌细胞（VSMC）的异常稳态和增殖是导致心脏病发作和中风等血管疾病的特征。在这里，我们通过重建单细胞转录组学和表观遗传谱分析的基因调控网络，阐明了调控 VSMC 增殖的分子决定因素。我们在增殖倾向的 VSMC 中检测到与疾病相关的基因座上广泛激活的增强子。我们比较了损伤反应性和非反应性 VSMC 之间的基因调控网络重排，这表明 VSMC 状态之间存在共享的转录因子，但靶基因座不同。通过计算机模拟干扰分析，我们确定并优先考虑了增殖的先前未被识别的调控因子，包括 RUNX1 和 TIMP1。此外，我们表明，先驱转录因子 RUNX1 增加了 VSMC 的反应性，而 TIMP1 通过 CD74 介导的 STAT3 信号反馈促进 VSMC 增殖。RUNX1 和 TIMP1-CD74 轴在人 VSMC 中表达，在正常动脉中表达水平较低，在疾病中表达水平升高，提示其具有临床相关性和作为血管疾病靶点的潜力。
