增强全球监管网络,将非编码乳腺癌基因与癌症基因连接起来
Yihan Wang1, Daniel Armendariz1, Lei Wang1
1Cecil H. and Ida Green Center for Reproductive Biology Sciences.
bioRxiv : the preprint server for biology
|December 4, 2023
概括
数以千计的乳腺癌增强剂使用单细胞CRISPRi屏幕进行了功能性特征. 这些增强剂调节癌症基因程序并形成复杂的网络,揭示亚型特异性功能并推进对乳腺癌发展的理解.
科学领域:
- 基因组学就是基因组学.
- 癌症生物学 癌症生物学
- 分子遗传学 分子遗传学
背景情况:
- 数以千计与乳腺癌相关的遗传变异存在于增强剂中.
- 这些增强剂的功能性特征在很大程度上缺失,阻碍了对它们在癌症中的作用的理解.
- 变异相关增强剂对转录表型的影响尚不清楚.
研究的目的:
- 在乳腺癌中使用单细胞CRISPRi屏幕功能性地表征3,512个变异相关的调节元素.
- 研究这些增强剂如何影响转录表型和癌症基因表达.
- 阐明增强剂形成的网络结构及其与癌症基因的调节关系.
主要方法:
- 在两个乳腺癌细胞系中对3,512个调节元件进行了全基因组的单细胞CRISPR干扰 (CRISPRi) 选.
- 分析了超过50万个单细胞转录组,以评估增强器扰动的影响.
- 利用比较分析来确定特定亚型的增强功能 (ER+与ER-细胞).
- 开发了pySpade包,用于分析单细胞增强器屏幕数据.
主要成果:
- 变异相关增强剂的扰乱显著破坏了乳腺癌基因程序.
- 确定了直接和间接调节癌症基因表达的增强剂.
- 发现了一对多和多对一网络模式,包括多个增强剂间接调节TP53.
- 在雌激素受体阳性 (ER+) 和雌激素受体阴性 (ER-) 乳腺癌细胞中表现出特定亚型增强功能.
结论:
- 变异相关增强剂是乳腺癌基因程序的关键调节者.
- 增强剂形成复杂的调节网络,将癌症基因连接起来,有助于乳腺癌的发展.
- 了解增强器网络及其亚型特定功能的理解,可以更全面地了解乳腺癌的病因.
- 该pySpade包促进了单细胞增强剂查的未来研究.
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