Porras-Tobias Ana L, Caldera Abigail, Castro-Piedras Isabel
Center for Biotechnology and Genomics, Texas Tech University, Lubbock, TX 79409, USA.
Genes (Basel). 2025 Aug 21;16(8):986. doi: 10.3390/genes16080986.
For 40 years, Intron Retention (IR) was dismissed as splicing noise and is now recognized as a dynamic and evolutionarily conserved mechanism of post-transcriptional gene regulation. Unlike canonical splicing, which excises all introns from pre-mRNAs, IR selectively retains intronic sequences, albeit at seemingly random places; however, current research now reveals that this process is strategic in its retention. IR influences mRNA stability, localization, and translational potential. Retained introns can lead to nonsense-mediated decay, promote nuclear retention, or give rise to novel protein isoforms that contribute to expanding proteomic and transcriptomic profiles. IR is finely regulated by splice site strength, splicing regulatory elements, chromatin structure, methylation patterns, RNA polymerase II elongation rates, and the availability of co-transcriptional splicing factors. IR plays critical roles in cell-type and tissue-specific gene expression with observed patterns, particularly during neuronal, cardiac, hematopoietic, and immune development. It also functions as a molecular switch during cellular responses to environmental and physiological stressors such as hypoxia, heat shock, and infection. Dysregulated IR is increasingly associated with cancer, neurodegeneration, aging, and immune dysfunction, where it may alter protein function, suppress tumor suppressor genes, or generate immunogenic neoepitopes. Experimental and computational tools like RNA-seq, RT-PCR, IRFinder, and IntEREst have enabled transcriptome-wide detection and validation of IR events, uncovering their widespread functional roles. This review will examine current knowledge on the function, regulation, and detection of IR, and also summarize recent advances in understanding its role in both normal and pathophysiological settings.
四十年来，内含子保留（IR）一直被视为剪接噪音，而现在它被公认为是一种动态且在进化上保守的转录后基因调控机制。与从信使核糖核酸前体（pre-mRNAs）中切除所有内含子的经典剪接不同，IR 会选择性地保留内含子序列，尽管这些序列似乎位于随机位置；然而，当前的研究表明，这一过程在其保留方面是有策略性的。IR 会影响信使核糖核酸的稳定性、定位和翻译潜力。保留的内含子可导致无义介导的衰变，促进核内保留，或产生新的蛋白质异构体，从而有助于扩展蛋白质组和转录组图谱。IR 受到剪接位点强度、剪接调控元件、染色质结构、甲基化模式、核糖核酸聚合酶 II 延伸率以及共转录剪接因子可用性的精细调控。IR 在细胞类型和组织特异性基因表达中发挥关键作用，呈现出特定的模式，尤其是在神经元、心脏、造血和免疫发育过程中。它在细胞对缺氧、热休克和感染等环境和生理应激源的反应中也起到分子开关的作用。IR 失调与癌症、神经退行性变、衰老和免疫功能障碍的关联日益增加，在这些情况下，它可能改变蛋白质功能、抑制肿瘤抑制基因或产生免疫原性新抗原表位。诸如核糖核酸测序（RNA-seq）、逆转录聚合酶链反应（RT-PCR）、IRFinder 和 IntEREst 等实验和计算工具，已实现了对 IR 事件的全转录组检测和验证，揭示了它们广泛的功能作用。本综述将探讨关于 IR 的功能、调控和检测的当前知识，并总结在理解其在正常和病理生理环境中的作用方面的最新进展。
