影响RNA稳定性的基因变异会影响复杂性状和疾病风险。

Genetic variants affecting RNA stability influence complex traits and disease risk.

作者信息

Huang Elaine, Fu Ting, Zhang Ling, Yan Guanao, Yamamoto Ryo, Terrazas Sari, Nguyen Thuy Linh, Gonzalez-Figueroa Carlos, Khanbabaei Armen, Bahn Jae Hoon, Varada Rajagopal, Amoah Kofi, Hervoso Jonatan, Paulsen Michelle T, Magnuson Brian, Ljungman Mats, Li Jingyi Jessica, Xiao Xinshu

机构信息

Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.

Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.

出版信息

Nat Genet. 2025 Sep 5. doi: 10.1038/s41588-025-02326-8.

DOI:10.1038/s41588-025-02326-8

PMID:40913182

Abstract

Gene expression is modulated jointly by transcriptional regulation and messenger RNA stability, yet the latter is often overlooked in studies on genetic variants. Here, leveraging metabolic labeling data (Bru/BruChase-seq) and a new computational pipeline, RNAtracker, we categorize genes as allele-specific RNA stability (asRS) or allele-specific RNA transcription events. We identify more than 5,000 asRS variants among 665 genes across a panel of 11 human cell lines. These variants directly overlap conserved microRNA target regions and allele-specific RNA-binding protein sites, illuminating mechanisms through which stability is mediated. Furthermore, we identified causal asRS variants using a massively parallel screen (MapUTR) for variants that affect post-transcriptional mRNA abundance, as well as through CRISPR prime editing approaches. Notably, asRS genes were enriched significantly among a multitude of immune-related pathways and contribute to the risk of several immune system diseases. This work highlights RNA stability as a critical, yet understudied mechanism linking genetic variation and disease.

摘要

基因表达由转录调控和信使核糖核酸稳定性共同调节，但后者在基因变异研究中常常被忽视。在此，我们利用代谢标记数据（Bru/BruChase-seq）和一种新的计算流程RNAtracker，将基因分类为等位基因特异性RNA稳定性（asRS）或等位基因特异性RNA转录事件。我们在11种人类细胞系组成的一个面板中的665个基因中鉴定出了5000多个asRS变异。这些变异直接重叠保守的微小RNA靶区域和等位基因特异性RNA结合蛋白位点，阐明了稳定性被介导的机制。此外，我们使用大规模平行筛选（MapUTR）来寻找影响转录后信使核糖核酸丰度的变异，以及通过CRISPR碱基编辑方法来鉴定因果asRS变异。值得注意的是，asRS基因在众多免疫相关途径中显著富集，并导致几种免疫系统疾病的风险增加。这项工作强调了RNA稳定性是连接基因变异和疾病的一个关键但未被充分研究的机制。