Abstract
Long non-coding RNAs (lncRNAs) are recognized as an important class of regulatory molecules involved in a variety of biological functions. However, the regulatory mechanisms of long non-coding genes expression are still poorly understood. The characterization of the genomic features of lncRNAs is crucial to get insight into their function. In this study, we exploited recent annotations by GENCODE to characterize the genomic and splicing features of long non-coding genes in comparison with protein-coding ones, both in human and mouse. Our analysis highlighted differences between the two classes of genes in terms of their gene architecture. Significant differences in the splice sites usage were observed between long non-coding and protein-coding genes (PCG). While the frequency of non-canonical GC-AG splice junctions represents about 0.8% of total splice sites in PCGs, we identified a significant enrichment of the GC-AG splice sites in long non-coding genes, both in human (3.0%) and mouse (1.9%). In addition, we found a positional bias of GC-AG splice sites being enriched in the first intron in both classes of genes. Moreover, a significant shorter length and weaker donor and acceptor sites were found comparing GC-AG introns to GT-AG introns. Genes containing at least one GC-AG intron were found conserved in many species, more prone to alternative splicing and a functional analysis pointed toward their enrichment in specific biological processes such as DNA repair. Our study shows for the first time that GC-AG introns are mainly associated with lncRNAs and are preferentially located in the first intron. Additionally, we discovered their regulatory potential indicating the existence of a new mechanism of non-coding and PCGs expression regulation.
Highlights
The genomes of distantly related species house remarkably similar numbers of protein-coding genes (PCGs) prompting the notion that many aspects of complex organisms arise from noncoding regions (Liu et al, 2013; Fatica and Bozzoni, 2014)
As genomic organization and gene structure may affect gene expression regulation, we characterized the genomic features of human and mouse long non-coding RNAs (lncRNAs) in comparison with PCGs
Our results did not appear to be driven by this bias as we used a recent and more complete GENCODE release, whose annotation was based on stronger experimental and computational evidence (Frankish et al, 2019) and they were confirmed in six more lncRNAs annotation datasets (FANTOM5, NONCODEv5, BIGTranscriptome, MiTranscriptome, LNCipedia, and LncBook)
Summary
The genomes of distantly related species house remarkably similar numbers of protein-coding genes (PCGs) prompting the notion that many aspects of complex organisms arise from noncoding regions (Liu et al, 2013; Fatica and Bozzoni, 2014). LncRNAs received growing attention as they emerged as an important regulatory layer of the transcriptome Anderson et al (2016) reported that the lack of transcription of the lncRNA Hand2os (Hand, opposite strand 1), but not the knockdown of its mature transcript, abolished the expression of the Hand (heart and neural crest derivatives expressed 2) gene leading to embryonic lethality in mice. Taken together, this evidence points toward the tight regulation of lncRNAs expression and the importance of lncRNAs transcription in regulating PCGs
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