MUC1-C通过调节癌症进展中的set1a指南针复合体来与表观遗传重编程交叉慢性炎症
Atrayee Bhattacharya1, Atsushi Fushimi1, Keyi Wang1
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Communications biology
|October 11, 2023
概括
由NF-κB激活的瘤性MUC1-C蛋白调节H3K4甲基化和COMPASS复合体,通过控制干性基因,将慢性炎症与癌症进展相结合.
科学领域:
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 癌症研究 癌症研究
背景情况:
- 慢性炎症通过不太了解的表观遗传重编程机制与癌症进展有关.
- 致癌性MUC1-C蛋白被癌细胞中的NF-κB通路激活.
- 之前还没有确定MUC1-C在调节COMPASS家族H3K4甲基转移酶中的作用.
研究的目的:
- 研究MUC1-C在慢性炎症和癌症期间表观遗传重编程中的作用.
- 阐明MUC1-C影响H3K4甲基化和COMPASS复合物的机制.
- 确定MUC1-C,NF-κB和AP-1在调节关键癌症相关基因中的参与.
主要方法:
- 通过NF-κB对MUC1-C对H3K4甲基化水平和COMPASS基因 (SET1A/SETD1A,WDR5) 的调节进行分析.
- 研究MUC1-C,WDR5和AP-1在驱动FOS,ATF3,TRAF1和RELB的表达中的作用.
- 评估MUC1-C,NF-κB,WDR5和AP-1对于KLF4和NOTCH1表达的必要性.
- 染色体免疫沉测定检查H3K4me3水平,染色体可访问性和KLF4和NOTCH1位置的转录.
主要成果:
- MUC1-C通过依赖NF-κB的机制调节大量H3K4甲基化和SET1A/SETD1A和WDR5基因的表达.
- MUC1-C和WDR5促进AP-1家族成员 (FOS,ATF3) 的表达,形成与NF-κB因子 (TRAF1,RELB) 的前循环.
- MUC1-C,NF-κB,WDR5和AP-1对于KLF4 (多能调节器) 和NOTCH1 (干效应因子) 的表达至关重要,增加H3K4me3,染色素可访问性和转录.
结论:
- MUC1-C直接调节SET1A COMPASS复合体,将NF-κB介导的慢性炎症与癌症进展联系起来.
- MUC1-C/NF-κB复合体招募SET1A/WDR5和AP-1来激活与多能性和干性有关的基因,例如KLF4和NOTCH1.1.
- 这些发现揭示了一个新的机制,MUC1-C将炎症信号与表观遗传变化结合起来,推动癌症的发展.
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