通过长读直接RNA测序揭示了E2调节的转录组复杂性:从异型发现到截断的蛋白质
Didem Naz Dioken1, Ibrahim Ozgul1, Irem Yilmazbilek1
1Department of Biological Sciences, Middle East Technical University (METU), Ankara, Türkiye.
RNA biology
|September 18, 2025
概括
长读测序揭示了ER+乳腺癌中的新型雌激素响应基因异型. 一种截断的TLE1蛋白质异型破坏了基因调节,并与较差的患者存活率有关.
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:
- 雌激素受体α (ERα) 阳性 (ER+) 乳腺癌是由雌激素信号驱动的,它调节了基因表达.
- 传统的测序方法在捕捉转录结构的全部复杂性方面存在局限性,阻碍了对雌激素敏感基因的完全理解.
研究的目的:
- 使用先进的测序技术,探索雌激素 (E2) 敏感转录组的景观及其蛋白质水平的影响.
- 识别和表征新型E2响应性异型,包括内在多基化 (IPA) 的mRNA,及其功能后果.
主要方法:
- 纳米孔长读直接RNA测序 (DRS) 与3'-end测序相结合.
- 在体外实验,基于深度学习的蛋白质建模,结构建模和基于蛋白质的测试.
- 功能性测试用于评估已识别的异构体对基因调节和患者生存数据分析的影响.
主要成果:
- 发现了包括IPAmRNA在内的多种E2响应编码和非编码RNA异型.
- 鉴定了一种TLE1的IPA异型,该异型产生C端截断蛋白,保留二分化,但缺乏WDR相互作用域.
- 证明截断的TLE1破坏了关键基因 (TFF1,GREB1) 的E2诱导上调,并且较低的IPA异型比率与ER+乳腺癌的生存率较差相关.
结论:
- 长读测序提供了对E2响应转录组的全面视图,揭示了新的调节机制.
- 截断的TLE1蛋白异型代表了ER+乳腺癌复杂性的新层,影响了基因调节和临床结果.
- 这些发现提供了对基因调节的见解,以及ER+乳腺癌中新治疗策略的潜在途径.
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