功能性基因组学将REST与内皮质可塑性和动脉样硬化联系起来
Maria Viskadourou1, Sharjeel Chaudhry1, Arianna Scalco1
1Division of Cardiology, Department of Medicine (M.V., S.C., A.S., P.R., P.T.-S., R.A., W.O., C.J.L., M.A.), Johns Hopkins University, Baltimore, MD.
Circulation research
|November 26, 2025
概括
研究人员发现,RE1沉默转录因子 (REST) 在内皮细胞中起到抑制作用,防止内皮细胞转变为介质细胞,并防止动脉样硬化. 这一发现为冠状动脉疾病的发病过程提供了新的见解.
科学领域:
- 遗传学和分子生物学
- 心血管研究研究心血管研究
- 细胞生物学 细胞生物学
背景情况:
- 全基因组关联研究 (GWAS) 已经确定了与冠状动脉疾病 (CAD) 病原体相关的众多位点.
- 这些GWAS关联的潜在分子机制,特别是在内皮细胞中,仍然在很大程度上未被探索.
研究的目的:
- 优先考虑与动脉样硬化相关的内皮特异性遗传位点,使用多特征同位化方法.
- 为了研究在CAD中针对RE1-沉默转录因子 (REST) 基因的已确定位点的功能作用.
主要方法:
- 在与动脉样硬化相关的细胞类型中,在表达量化特征位点 (eQTLs) 上应用了多特征同位化方法.
- 在实验室中利用了CRISPR干扰,Pcsk9-过度表达的小鼠模型与内皮特异性休息淘汰,和RNA测序 (RNA-seq).
- 执行单核RNA测序和Cleave under Targets和分类 (CUT&Tag) 测序以获得机械洞察力.
主要成果:
- 发现染色体4位点中的一个保存的调节元件通过降低内皮细胞中的REST表达来增加CAD风险.
- 在小鼠中,内皮特异性休息淘汰导致动脉样硬化斑块形成,巨细胞和脂质沉积增加.
- 在人类大动脉内皮细胞中,REST静音诱导了内皮到介质细胞的过渡 (EndMT),增加了透性和迁移,涉及L1CAM激活和TGFb信号传递.
结论:
- RE1抑制转录因子 (REST) 在内皮细胞中起到关键的抑制作用.
- REST 构成性地抑制了内皮细胞到介质酶的过渡 (EndMT),从而防止动脉样硬化.
- 这些发现揭示了REST在心血管健康中的新型保护作用.
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