在Rhabdomyosarcoma表达中需要SNAI2/CTCF相互作用NOTCH1表达
Prethish Sreenivas1, Long Wang1, Meng Wang2
1Greehey Children's Cancer Research Institute, Department of Molecular Medicine, University of Texas Health Sciences Center, San Antonio, Texas, USA.
科学家们发现了SNAI2和CTCF如何通过调节亚TAD边界,影响细胞活力和分化来维持NOTCH1在聚变负性狂肌肉瘤 (FN-RMS) 中的表达.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 肌肉骨髓瘤 (RMS) 是一种儿科肌肉癌,细胞无法分化.
- NOTCH1,一种瘤基因,驱动自我更新并阻断聚变负RMS (FN-RMS) 的分化.
- 在RMS瘤中NOTCH1的转录调节仍然不清楚.
研究的目的:
- 为了阐明维持NOTCH1表达在FN-RMS中的机制.
- 调查SNAI2和CTCF在NOTCH1法规中的作用.
- 了解SNAI2/NOTCH1对RMS细胞活力,分化和辐射敏感性的影响.
主要方法:
- 染色体免疫沉 (ChIP) 用于SNAI2和CTCF结合.
- 使用Hi-C分析来识别拓关联域 (TAD).
- 用CRISPR/Cas9和shRNA进行基因切除和淘汰;细胞活力测定;重新引入NOTCH1变异.
主要成果:
- 一个保存的SNAI2/CTCF结合峰值在NOTCH1下游标志着NOTCH1表达和FN-RMS细胞活力所必需的子TAD边界.
- 删除这个峰值取消了NOTCH1表达和细胞活力,可以通过重新引入激活的NOTCH1.1来恢复.
- SNAI2 除导致细胞损失,但幸存的细胞重新建立NOTCH1表达,显示差异化受损,但持续的辐射敏感性.
- 在抑制辐射后亡中SNAI2的作用独立于它对自我更新和分化的影响.
结论:
- SNAI2和CTCF通过建立一个子TAD边界来维持NOTCH1的表达,这对FN-RMS瘤发生至关重要.
- 在调节NOTCH1表达和抑制辐射诱导的亡方面,SNAI2发挥着双重作用.
- 针对SNAI2或NOTCH1可能是FN-RMS的潜在治疗策略.
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