背景定义的癌症共同依赖映射确定了淋巴瘤中PRC2和MLL-MEN1复合体之间的功能相互作用
Xiao Chen1,2, Yinglu Li1, Fang Zhu1,3
1Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, 10032, USA.
Nature communications
|July 17, 2023
概括
研究人员使用CRISPR屏幕绘制了基因依赖关系,以发现新的染色质交叉交叉机制. 他们发现了PRC2和MLL-MEN1复合体之间的意想不到的联系,揭示了癌症的新治疗点.
科学领域:
- 表观遗传学和染色体生物学
- 癌症基因组学 癌症基因组学
- 系统生物学 系统生物学
背景情况:
- 染色质修饰和复合体定义了表观基因组领域,但交叉通话机制仍然不太了解.
- 了解动态色素状态转换对于发育和疾病研究至关重要.
研究的目的:
- 系统地识别基因与基因的功能关系和染色体交叉机制.
- 定义癌症中必不可少的基因模块的分子背景.
主要方法:
- 基于CRISPR-Cas9的健身屏幕用于泛癌细胞系的相互依赖映射.
- 突变,表观基因组,基因表达和药物敏感性数据的整合.
- 分析蛋白质复合体的组成和功能.
主要成果:
- 确定了145个共同依赖模块和新的功能互动.
- 发现了多镇压复合体2 (PRC2) 和MLL-MEN1复合体之间的意想不到的共同依赖.
- 已证明PRC2介导的H3K27三甲基化调节了MLL1/MEN1全基因组分布.
- 淋巴瘤细胞中显示的EZH2突变导致MLL-MEN1重新定位,驱动瘤发生和MEN1抑制剂敏感性.
结论:
- 为发现染色体调节中的跨调节性相互作用提供了一个资源.
- 突出了PRC2-MLL-MEN1交叉作为染色体调节的机制.
- 确定潜在的合成致死性目标,特别是在特定淋巴瘤情况下的MEN1抑制.
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