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在内皮细胞中,FOXO1刺激尖端细胞丰富基因表达

Yuri Miyamura¹, Shunsuke Kamei¹, Misaki Matsuo²

¹Divison of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, Japan.

|March 6, 2024

概括

叉头盒O1 (FOXO1) 蛋白调节内皮细胞 (EC) 尖端细胞的形成和血管发育. 这项研究揭示了FOXO1

科学领域:

分子生物学分子生物学
细胞生物学细胞生物学
发展生物学发展生物学

背景情况:

叉头盒O (FOXO) 蛋白质是细胞功能的关键调节者,包括新陈代谢,亡和衰老.
对于胚胎发育来说,FOXO1是必不可少的,而没有FOXO1的小鼠由于内皮细胞 (EC) 成熟和血管重塑的缺陷而导致死亡.
在EC中,特别是血管发育中,FOXO1的精确全基因组调节机制仍然不完全理解.

研究的目的:

阐明FOXO1在血管发育过程中的内皮细胞 (ECs) 中的全基因组调节作用.
研究血管内皮生长因子 (VEGF) 对FOXO1的动态调节及其对EC功能的下游影响.
在VEGF介导的尖端细胞规范的背景下,识别由FOXO1控制的特定基因和调控区域.

主要方法:

使用RNA测序 (RNA-seq) 结合FOXO1过度表达和初级培养ECs的淘汰.
进行了染色体免疫沉测序 (ChIP-seq) 来绘制全基因组内源性FOXO1结合位.
研究了对VEGF刺激的反应中FOXO1转位动态,并确定了涉及PP2A酸酶的调节途径.

主要成果:

证明VEGF通过PP2A酸酶的介导动态调节EC中细胞质和细胞核之间的FOXO1转位.
确定FOXO1是VEGF响应型,尖端细胞丰富基因的关键调节者,也是DLL4-NOTCH信号的负调节者.
FOXO1 ChIP-seq显示直接结合EC独特的尖端丰富基因,与EC主调节器在凝结色素区域共定位,充当先驱因素. 确定ESM1和ANGPT2为新型FOXO1调节目标.

结论:

这项研究提供了FOXO1在初级EC中的第一个细胞类型特定的功能性特征.
通过调节特定的基因表达程序,FOXO1在定义VEGF介导的尖端细胞身份方面发挥着关键作用.
FOXO1充当先驱因素,与可访问的染色体区域结合,以控制参与血管尖端细胞形成的关键基因的表达.

关键词:

细胞生物学细胞生物学分子生物学分子生物学

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