混合模型和全转录组关联分析确定与结直肠癌易感性相关的转录因子和基因
Zhishan Chen1, Wenqiang Song1,2, Qing Li1
1Division of Epidemiology, Department of Medicine,sss Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
Nature communications
|January 15, 2026
概括
这项研究确定了关键的转录因子 (TF) 和它们的相互作用,调节结直肠癌 (CRC) 风险. 它揭示了新的CRC风险基因和潜在的治疗点,进步了我们对CRC病变的理解.
科学领域:
- 遗传学和基因组学 遗传学和基因组学
- 癌症生物学 癌症生物学
- 分子生物学分子生物学
背景情况:
- 影响结肠直肠癌 (CRC) 风险基因的遗传变异通常由转录因子 (TFs) 与改变的DNA结合介导.
- 识别这些特定的TF及其监管作用对于理解CRC易受性至关重要.
研究的目的:
- 为了确定转录因子 (TF) 和调节结直肠癌 (CRC) 风险的TF-辅因子相互作用.
- 通过将TF结合数据与基因表达和拼接集成,发现新的CRC风险基因和潜在的治疗标.
- 为了功能验证已识别的CRC风险基因.
主要方法:
- 对218 TF ChIP-Seq数据集和来自东亚和欧洲大型队列的全基因组关联研究 (GWAS) 数据的分析.
- 与全转录组关联研究 (TWAS) 的整合,使用RNA-seq数据来评估遗传预测的基因表达,替代拼接和多化.
- 单细胞分析和实验验证 (例如,对于RHPN2,IRS2,TXN) 来确认致癌作用.
主要成果:
- 确定51个关键的TF和TF辅助因子相互作用,包括VDR辅助因子,调节CRC风险.
- 通过多祖先TWAS发现了222个CRC风险基因,包括95个新型基因和48个潜在的药物标.
- 通过单细胞分析和实验验证的功能证据支持约45%的鉴定基因,证实了RHPN2,IRS2和TXN的致癌作用.
结论:
- 揭示了关键的TF基因调节网络,这些网络与结直肠癌 (CRC) 病原发生有关.
- 发现新型的基因和分子参与者有助于CRC风险.
- 为开发向治疗和改善结直肠癌风险预测提供了基础.
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