H3K27me3 染色质异质性揭示了细胞对雌激素和内分泌治疗的可变反应
Fleur Chapus1, Christopher R Day1, Laura G Kammel1
1Epigenetics and RNA Biology Laboratory, Single Cell Dynamics Group, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA.
bioRxiv : the preprint server for biology
|September 26, 2025
概括
雌激素受体α阳性乳腺癌中的基因表达异质是由抑制性染色体驱动的. 这导致TFF1基因不活,降低药物敏感性和内分泌抵抗.
科学领域:
- 分子生物学分子生物学
- 基因组学就是基因组学.
- 癌症研究 癌症研究
背景情况:
- 基因表达异质性产生了逃避治疗的瘤细胞亚群.
- 雌激素受体α阳性 (ERα+) 乳腺瘤表现出显著的异质性.
- 了解基因表达变异性对于开发有效的癌症疗法至关重要.
研究的目的:
- 确定调节ERα+乳腺癌中TFF1基因表达异质性的分子机制.
- 调查染色质状态在TFF1表达变异性中的作用.
- 确定TFF1表达水平与内分泌治疗反应之间的联系.
主要方法:
- 根据TFF1活动水平排序的细胞分析.
- 对于H3K27me3.3的染色体免疫沉 (ChIP) 的研究.
- 在TFF1监管元素中对ERα结合的量化.
- 评估转录突破频率和基因表达水平.
主要成果:
- 不活跃的TFF1 (TFF1low) 细胞在TFF1促进剂和增强剂中显示抑制性染色素 (H3K27me3).
- 在 TFF1 低细胞中的 TFF1 调控元素中减少了 ERα 的占用.
- TFF1低细胞表现出减少的转录破裂和对内分泌治疗的敏感性降低.
- 活跃的TFF1 (TFF1高) 细胞显示更多活跃的等位基因和超爆发,保持药物敏感性.
结论:
- 抑制性染色体动力学,特别是H3K27me3丰富,驱动ERα+乳腺癌中的基因表达异质性.
- 这种异质性有助于通过创建TFF1低的亚群,降低药物反应,从而导致内分泌抵抗.
- 染色体状态是一个关键的调节器,将基因表达变异性与治疗耐药性联系起来.
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