抑制EZH2刺激了静止脏B细胞中的重复元素表达和病毒模拟
Seung J Kim1,2,3, Patti K Kiser4, Samuel Asfaha1,2,4,5
1London Regional Cancer Program, Children's Health Research Institute, London, ON, Canada.
The EMBO journal
|November 7, 2023
概括
在B细胞中抑制EZH2会通过炎症性化学因子触发重复元素误表和细胞死亡. 这种反应模仿病毒感染,由模式识别受体调节.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 免疫学 免疫学 免疫学
- 基因组学就是基因组学.
背景情况:
- 哺乳动物细胞通常通过 heterochromatin 形成来沉默重复的基因组序列.
- 这些重复元素的异常表达的影响尚未完全理解.
- B细胞具有独特的表观遗传特征,包括高H3K27me3和低DNA甲基化在重复,使他们对EZH2抑制敏感.
研究的目的:
- 研究EZH2抑制对B细胞重复表达和细胞活性的影响.
- 阐明模式识别受体 (RIG-I,MDA5,cGAS) 在细胞对EZH2抑制和重复错误表达的反应中的作用.
- 探索EZH2抑制诱导炎症反应和病毒模拟的潜力.
主要方法:
- 在野生型和新型模式识别受体功能丧失小鼠模型 (RIC) 中使用EZH2抑制剂,具有Rigi,Ifh1和Cgas.的突变.
- 评估了基因素H3氨酸27三甲基化 (H3K27me3) 和重复元素表达的变化.
- 量化NF-κB依赖的化学激素表达和细胞死亡途径.
主要成果:
- 抑制EZH2导致H3K27me3的减少,并在野生型和RIC突变B细胞中增加重复元素表达.
- RIC突变抑制了NF-κB依赖的炎症性化学激素表达和随后由EZH2抑制诱导的细胞死亡.
- 发现模式识别受体对于激活癌细胞在EZH2抑制时的干扰素反应至关重要.
结论:
- 在B细胞中抑制EZH2会诱导一种新型的炎症反应,其特征是基因基因表达,由基因组重复错误表达触发.
- 这种EZH2抑制剂诱导的反应表现出病毒模拟的特征,特别是考虑到与爱斯坦-巴尔病毒诱导的基因的重叠.
- 模式识别受体在抑制EZH2后的炎症和细胞死亡结果中起着关键作用,将表观遗传失调与先天免疫感知联系起来.
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