Chang Tyron, Hancks Dustin C
Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA.
Genetics, Development, and Disease Ph.D. Program, UT Southwestern Medical Center, Dallas, TX, USA.
BMC Genomics. 2025 Sep 26;26(1):827. doi: 10.1186/s12864-025-11982-3.
Small RNAs regulate gene expression in species across the tree of life. miRNAs, which impact a variety of cellular and physiological processes ranging from development and stress adaptation to host defense, are one of the best characterized classes of small RNA. Many miRNAs are produced from longer non-coding transcripts generated from host genes via a series of RNA cleavage reactions. The location of a small RNA within a host gene can shape the processing of the mature small RNA. For example, a type of miRNAs derived from host gene intronic sequence, referred to as miRtrons, are Drosha-independent and reliant on splicing for biogenesis. Relatedly, processing of a small RNA from an exon of a protein-coding mRNA, in principle, may destabilize it and compromise translation of the host gene. Prior to extensive transcriptome analysis, informatics analyses identified six human miRNAs embedded in exons of protein-coding genes and experimental studies have characterized additional anecdotal examples. Still, whether protein-coding mRNAs encoding small RNAs represent an appreciable class of host genes given the now recognized complexity of the transcriptome is unclear.
Our analysis finds 201 small RNAs (118 human and 83 mouse) encoded by expressed exons of protein-coding genes (5'-UTR, CDS, 3'-UTR). Forty-six of these cases (29 human and 17 mouse) are also present in MirGeneDB which includes the most up-to-date miRNA classifications. Many of these small RNAs are poorly characterized with 96% of the protein-coding host gene relationships identified here not previously known. Furthermore, the identification of nearly fifty human and mouse small RNAs embedded within coding exons of canonical ORFs suggests that overlapping hybrid genes might be more common than previously appreciated in higher organisms. Expression analysis for a subset of these small RNAs indicates that many display differential expression across human tissues with the pattern correlating significantly with the expression of the candidate protein-coding host gene.
Overall, our analysis suggests that the number of protein-coding transcripts serving as host genes is greater than previously recognized. Our small RNA host gene classifications may serve as a resource to shed new light on small RNA biology, specific host genes, and gene regulation.
小RNA在整个生命之树的物种中调控基因表达。微小RNA（miRNA）是特征最明确的小RNA类别之一，它影响从发育、应激适应到宿主防御等多种细胞和生理过程。许多miRNA由宿主基因通过一系列RNA切割反应产生的较长非编码转录本加工而来。宿主基因内小RNA的位置会影响成熟小RNA的加工过程。例如，一类源自宿主基因内含子序列的miRNA，称为内含子miRNA（miRtron），其加工不依赖于Drosha，而是依赖剪接进行生物合成。相关地，从蛋白质编码mRNA的外显子加工小RNA，原则上可能会使其不稳定并损害宿主基因的翻译。在进行广泛的转录组分析之前，信息学分析鉴定出6个人类miRNA嵌入在蛋白质编码基因的外显子中，实验研究也发现了其他一些个别例子。然而，鉴于目前已认识到的转录组复杂性，编码小RNA的蛋白质编码mRNA是否代表一类可观的宿主基因尚不清楚。
我们的分析发现201个小RNA（118个人类和83个小鼠）由蛋白质编码基因的表达外显子（5'-UTR、CDS、3'-UTR）编码。其中46个例子（29个人类和17个小鼠）也存在于包含最新miRNA分类的MirGeneDB中。这些小RNA中的许多特征尚不明确，此处鉴定的蛋白质编码宿主基因关系中96%以前未知。此外，在标准开放阅读框（ORF）的编码外显子中鉴定出近五十个人类和小鼠小RNA，这表明重叠杂交基因在高等生物中可能比以前认为的更为常见。对这些小RNA中的一部分进行表达分析表明，许多小RNA在不同人体组织中表现出差异表达，其模式与候选蛋白质编码宿主基因的表达显著相关。
总体而言，我们的分析表明作为宿主基因的蛋白质编码转录本数量比以前认识到的更多。我们对小RNA宿主基因的分类可能为深入了解小RNA生物学、特定宿主基因和基因调控提供资源。
