Bone Max, Inman Gareth J
School of Cancer Sciences, University of Glasgow, United Kingdom.
Cancer Research UK Scotland Institute, Glasgow, United Kingdom.
Noncoding RNA Res. 2025 May 3;14:38-50. doi: 10.1016/j.ncrna.2025.04.008. eCollection 2025 Oct.
Transcriptional start and end variance, a less-explored aspect of lncRNA biology, is a critical determinant of isoform diversity in human RNA. While alternative splicing (AS) has been extensively studied as a mechanism of isoform generation, differences in transcriptional start and termination site usage-whether from distinct promoters or varying initiation events at the same core promoter-contribute more to isoform diversity than alternative splicing. In the context of long non-coding RNAs (lncRNAs), even subtle alterations to transcriptional start and end sites can induce significant changes in the structural and functional capacities of individual lncRNA isoforms. This review highlights the underappreciated realm of transcriptional start and end variance in lncRNAs, exploring its pivotal role in shaping the diversity of lncRNA transcripts. In cancer, where lncRNAs are increasingly recognised as key players in tumorigenesis, understanding the ramifications of transcriptional start and end variance is crucial. With single nucleotide alterations capable of influencing the folding energy, shape, stability, and function of a lncRNA molecules, significant changes to transcriptional regulation may lead to aberrant isoforms with implications for cancer initiation, progression, and potentially, its treatment. As lncRNAs emerge as therapeutic targets, particularly with the advancement of antisense oligonucleotide (ASO) technologies, it becomes crucial to understand the regulatory landscape of transcriptional variation among lncRNA isoforms, to ensure selective targeting of oncogenic transcripts while sparing those with normal physiological functions. By highlighting the significance of transcriptional start and end site variation as major contributors to lncRNA diversity, the potential exploitation for precision therapeutic interventions in the field of non-coding RNA cancer research can be expanded.
转录起始和终止变异是长链非编码RNA（lncRNA）生物学中一个较少被探索的方面，是人类RNA中异构体多样性的关键决定因素。虽然可变剪接（AS）作为异构体产生的一种机制已被广泛研究，但转录起始和终止位点使用的差异——无论是来自不同的启动子还是同一核心启动子处不同的起始事件——对异构体多样性的贡献比可变剪接更大。在长链非编码RNA（lncRNA）的背景下，即使转录起始和终止位点发生细微改变，也可能导致单个lncRNA异构体的结构和功能能力发生显著变化。本综述强调了lncRNA中转录起始和终止变异这一未得到充分重视的领域，探讨了其在塑造lncRNA转录本多样性中的关键作用。在癌症中，lncRNA越来越被认为是肿瘤发生的关键因素，了解转录起始和终止变异的影响至关重要。由于单核苷酸改变能够影响lncRNA分子的折叠能量、形状、稳定性和功能，转录调控的显著变化可能导致异常异构体，对癌症的发生、发展以及潜在的治疗产生影响。随着lncRNA成为治疗靶点，特别是随着反义寡核苷酸（ASO）技术的进步，了解lncRNA异构体之间转录变异的调控格局变得至关重要，以确保在保留具有正常生理功能的转录本的同时，选择性靶向致癌转录本。通过强调转录起始和终止位点变异作为lncRNA多样性主要贡献者的重要性，可以扩大非编码RNA癌症研究领域中精准治疗干预的潜在应用。
