持续的基因表达和DNA甲基化变化与二酸的致癌作用有关
Gleta Carswell1, John Chamberlin1,2, Brian D Bennett3
1Center for Computational Toxicology and Exposure, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States.
Frontiers in oncology
|May 20, 2024
概括
双酸 (DCA) 暴露会改变小鼠的基因表达和DNA甲基化,增加肝脏瘤的风险. 这些表观遗传变化持续存在,影响细胞通路并促进瘤发生,特别是在生命早期暴露时.
科学领域:
- 毒理学和环境健康
- 表观遗传学和基因组学
- 癌症生物学 癌症生物学
背景情况:
- 了解短暂暴露是识别疾病特征的关键.
- 二乙酸 (DCA) 是一种新陈代谢重编程剂,以前已经证明可以增加小鼠的肝脏瘤发病率.
研究的目的:
- 调查二乙酸 (DCA) 暴露引起的转录组和表观组变化.
- 将这些分子变化与先前观察到的表型结果联系起来,特别是肝脏瘤发病率.
主要方法:
- 使用了从暴露于DCA的小鼠获得的已存档的甲固定肝样本.
- 通过向RNA测序 (TempO-seq) 测量基因表达,并通过减少表示双硫酸盐测序 (RRBS) 测量DNA甲基化.
- 分析了来自不同暴露时间和戒备期的样本.
主要成果:
- 转录和DNA甲基化变化在暴露时间点附近最为明显,在DCA停止后有所减弱.
- 基因通路分析揭示了氧化代谢的影响,特别是在生命早期暴露后.
- 在生命的后期,基因特征和通路转向亲瘤原生模式,与持续的DNA甲基化变化相关.
结论:
- DCA诱导的肝脏代谢重编程与衰老过程相互作用.
- 连续和先前的DCA暴露都会增加雄性B6C3F1小鼠的瘤负担.
- 表观遗传变化表明在DCA相关的瘤发生中具有持久的调节作用.
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