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在初级人类冠状细胞中响应拼接QTLs识别了假定的骨关节炎风险基因

Seyoun Byun¹, Philip Coryell², Nicole Kramer^1,2

¹Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27599, USA.

bioRxiv : the preprint server for biology

|November 28, 2024

概括

替代拼接显著影响骨关节炎 (OA) 的发展,纤维内素片段 (FN-f) 触发了OA类拼接事件. 这项研究通过分析拼接定量特征位点 (sQTLs) 来确定新型OA风险基因和潜在的治疗标.

科学领域:

遗传学是一个遗传学.
分子生物学分子生物学
骨关节炎研究骨关节炎研究

背景情况:

骨关节炎 (OA) 影响全球数百万人,其分子基础不明,阻碍了有效的治疗开发.
全基因组关联研究 (GWAS) 已经确定了许多与OA相关的遗传位置,但确定特定的因果基因仍然是一个挑战.
以前的研究探讨了关节炎的表达定量特征位点 (eQTL),但替代拼接在关节炎发病过程中的作用在很大程度上未被研究.

研究的目的:

研究替代拼接在骨关节炎发病过程中的作用和影响.
为了识别基因和分子机制受影响的替代拼接在OA触发的反应.
将拼接定量特征位点 (sQTL) 数据与OA GWAS集成,以发现新的OA风险基因.

主要方法:

进行了RNA测序 (RNA-seq),对101个用对照剂 (PBS) 或纤维素片段 (FN-f) 治疗的人类软骨细胞样本进行了测序,这是一种OA触发物.
不同拼接分析确定了在条件之间具有改变拼接模式的基因.
使用CRISPR/Cas9功能验证一个特定的拼接事件.
基因型化数据被整合,以确定拼接定量特征位点 (sQTLs) 和它们与OA GWAS变体的关联.

主要成果:

总共有590个不同的拼接基因被确定,FN-f治疗诱导了类似于初级OA组织的拼接模式.
通过CRISPR/Cas9模拟SNRNP70拼接事件,导致了类似OA的表达模式.
发现了7,188个影响3,056个基因的sQTL,包括特定疾病的sQTL.
与OA GWAS数据的同位定位确定了6个假定OA风险基因,特别是包括新型候选PBRM1.

结论:

替代拼接在骨关节炎的发病过程中起着重要作用.
纤维蛋白片段诱导的替代拼接事件反映了在人类OA组织中观察到的事件.
该研究为了解拼接对OA的贡献提供了基础,并确定了潜在的治疗点,包括PBRM1.1.

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