综合功能基因组学揭示了代谢性肝病风险等位基因的转录调节功能
Wenxiang Hu1, Biying Zhu1, Na He1
1Guangzhou National Laboratory.
Research square
|November 24, 2025
概括
研究人员发现了非编码DNA中的遗传变异如何影响代谢功能障碍相关的脂肪性肝病 (MASLD). 这些变异改变基因表达,影响脂质代谢和疾病风险.
科学领域:
- 基因组学就是基因组学.
- 肝病学 肝病学是一种肝病学.
- 分子生物学分子生物学
背景情况:
- 全基因组关联研究 (GWAS) 已经确定了许多与代谢功能障碍相关的脂肪性肝病 (MASLD) 相关的位置.
- 遗传变异的功能作用,特别是在非编码区域,仍然在很大程度上是未知的.
- 了解这些变异对于阐明MASLD病原体至关重要.
研究的目的:
- 研究非编码基因变异对MASLD.有助于形成的分子机制.
- 确定与MASLD风险变异相关的细胞类型特定的调控元素和转录因子结合位.
- 将已识别的变异与功能目标基因联系起来,以及它们在脂质代谢和肝脏病理学中的作用.
主要方法:
- 来自MASLD患者的肝细胞核的染色质可访问性概况.
- 大规模并行报告测试 (MPRA) 用于识别差异性活动变体 (DAV).
- 综合性分析包括肝脏eQTLs,染色质循环和单细胞CRISPRi查.
- 在关键代谢基因附近对DAV的功能验证.
主要成果:
- 鉴定了针对MASLD风险变体丰富的细胞类型特定的转录因子结合位.
- 发现了数百种DAVs以细胞类型和刺激依赖的方式影响转录性调节网络.
- 与关键脂质代谢调节者的基因表达调节相关的DAVs (例如SLC22A3,APOA5,ANGPTL3,LPL).
- 证明了DAVs对改变脂质代谢和肝星细胞激活的贡献.
- 展示了DAVs对MASLD疾病风险的预测能力.
结论:
- 非编码基因变异通过改变基因调节在MASLD病原体中发挥着重要作用.
- 基因组和功能数据的多式集成为MASLD监管机制提供了关键的见解.
- 这些发现为MASLD风险分层和治疗目标提供了潜在的生物标志物.
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