在小鼠中,ETV6抑制炎症反应基因,并在压力造血过程中调节HSPC功能
Mackenzie Bloom1,2, Ninad Oak2, Rebekah Baskin-Doerfler3
1St. Jude Graduate School of Biomedical Sciences, Memphis, TN.
Blood advances
|July 31, 2023
概括
生殖系ETV6变体通过未能抑制炎症基因而损害了造血干细胞和原生细胞 (HSPC) 功能,导致5型 (T5) 血小板缺血和白血病风险增加.
科学领域:
- 血液学 血液学 血液学
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- 造血干细胞和原始细胞 (HSPCs) 对于成年人造血至关重要.
- 生殖系ETV6变异会导致5型血小板缺血 (T5),这种情况与血小板低和白血病倾向有关.
- 通过ETV6变种影响HSPC的确切机制尚不清楚.
研究的目的:
- 调查生殖系ETV6变种如何影响HSPC功能并对T5.5有所贡献.
- 阐明ETV6在血液形成中的作用背后的分子机制.
主要方法:
- 生成了一个具有Etv6功能丧失变体 (Etv6R355X/+) 的小鼠模型,模仿人类T5变体.
- 使用串行竞争性移植试验来评估HSPC功能.
- 使用CUT&RUN,ATAC-seq和Hi-C来映射ETV6结合和染色体可访问性.
- 进行单细胞RNA测序以分析HSPCs中的基因表达变化.
主要成果:
- 移植后的Etv6R355X/+小鼠表现出改变的HSPC比例和受损的造血复合.
- 发现ETV6在HSPC中结合炎症基因位置,包括TNF信号通路基因.
- 与野生类型相比,Etv6R355X/+ HSPCs显示炎症基因的表达增加和TNF的产生增加.
结论:
- 在血液生成压力期间,ETV6对于抑制HSPCs炎症基因表达至关重要.
- 这种ETV6媒介抑制的失调会导致HSPC功能受损和T5的病原性.
- 维持ETV6功能对于持续的HSPC功能和预防血液恶性瘤至关重要.
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