美国芝加哥大学Yang I. Li团队揭示全局范围内无效剪接对人类基因表达的影响。该项研究成果于2024年9月2日在线发表在《自然—遗传学》杂志上。

研究人员表示，人类基因中的可变剪接（AS）通常被视为增强蛋白质多样性的一种机制。然而，AS也可以通过产生被无义介导的降解（NMD）迅速降解的“无效”转录本，影响基因表达水平而不增加蛋白质多样性。然而，这种调控机制的相对重要性尚未得到充分探索。

为了更好地理解AS-NMD相对于其他调控机制的影响，研究人员分析了涵盖从转录到胞质降解等不同阶段的八种分子检测的群体规模基因组数据。结果表明，与先前基于稳态RNA的估计相比，无效剪接的频率高出三倍。这种无效剪接在多内含子基因中积累，导致15%的编码蛋白质基因的转录分子是无效的。

通过分析细胞系中的遗传变异，研究人员发现与AS相关的GWAS性状相关位点同样经常与NMD诱导的表达水平差异相关，正如与蛋白质亚型使用的差异相关一样。这些研究结果表明，AS的许多影响是通过NMD诱导的基因表达变化，而不是通过蛋白质多样化来介导的。

附：英文原文

Title: Global impact of unproductive splicing on human gene expression

Author: Fair, Benjamin, Buen Abad Najar, Carlos F., Zhao, Junxing, Lozano, Stephanie, Reilly, Austin, Mossian, Gabriela, Staley, Jonathan P., Wang, Jingxin, Li, Yang I.

Issue&Volume: 2024-09-02

Abstract: Alternative splicing (AS) in human genes is widely viewed as a mechanism for enhancing proteomic diversity. AS can also impact gene expression levels without increasing protein diversity by producing ‘unproductive’ transcripts that are targeted for rapid degradation by nonsense-mediated decay (NMD). However, the relative importance of this regulatory mechanism remains underexplored. To better understand the impact of AS–NMD relative to other regulatory mechanisms, we analyzed population-scale genomic data across eight molecular assays, covering various stages from transcription to cytoplasmic decay. We report threefold more unproductive splicing compared with prior estimates using steady-state RNA. This unproductive splicing compounds across multi-intronic genes, resulting in 15% of transcript molecules from protein-coding genes being unproductive. Leveraging genetic variation across cell lines, we find that GWAS trait-associated loci explained by AS are as often associated with NMD-induced expression level differences as with differences in protein isoform usage. Our findings suggest that much of the impact of AS is mediated by NMD-induced changes in gene expression rather than diversification of the proteome.

DOI: 10.1038/s41588-024-01872-x

Source: https://www.nature.com/articles/s41588-024-01872-x