Abstract
RNA editing modifies the sequence of primary transcripts, potentially resulting in profound effects to RNA structure and protein-coding sequence. Recent analyses of RNA sequence data are beginning to provide insights into the distribution of RNA editing across the entire transcriptome, but there are few published matched whole genome and transcriptome sequence datasets, and designing accurate bioinformatics methodology has proven highly challenging. To further characterize the RNA editome, we analyzed 16 paired DNA-RNA sequence libraries from prostate tumor specimens, employing a comprehensive strategy to rescue low coverage sites and minimize false positives. We identified over a hundred thousand putative RNA editing events, a third of which were recurrent in two or more samples, and systematically characterized their type and distribution across the genome. Within genes the majority of events affect non-coding regions such as introns and untranslated regions (UTRs), but 546 genes had RNA editing events predicted to result in deleterious amino acid alterations. Finally, we report a potential association between RNA editing of microRNA binding sites within 3′ UTRs and increased transcript expression. These results provide a systematic characterization of the landscape of RNA editing in low coverage sequence data from prostate tumor specimens. We demonstrate further evidence for RNA editing as an important regulatory mechanism and suggest that the RNA editome should be further studied in cancer.
Highlights
The deregulation of post-transcriptional modification is increasingly recognized as a hallmark of cancer, generating enormous diversity and significantly affecting downstream activity
The detection of putative RNA editing events in next-generation sequence data is an emerging area of research, and we hypothesized that a deep systematic analysis of RNA-DNA sequence differences (RDDs) sites would provide novel insights into global RNA editing of the human transcriptome and guide future studies
We employed a stringent filtering strategy to minimize false positives, excluding predicted RDDs which were: i) known polymorphisms or mutations; ii) supported by any DNA-seq read from any specimen; iii) mapped to within 8 bp of splice sites; iv) better explained by murine contamination; and v) within regions aligning to paralogous genes or repeats
Summary
The deregulation of post-transcriptional modification is increasingly recognized as a hallmark of cancer, generating enormous diversity and significantly affecting downstream activity. RNA editing is a process by which the sequence of primary transcripts is modified, resulting in RNA-DNA sequence differences (RDDs). ARI editing is highly prevalent within inverted-repeated Alu elements due to their propensity to form double-stranded RNA structures [2,3]. RNA editing affects introns and untranslated regions (UTRs) of genic transcripts (partly due to the presence of Alu elements within these regions), where substitutions can modulate splicing or RNA structure [4,5]. A recent study reported that RDDs were enriched in 39UTRs and microRNA target sites in mouse tissues, suggestive of a regulatory role for RNA editing [6]. The most notable recurrently edited site falls within the second transmembrane domain of mammalian glutamate receptor subunits, where it results in a Q to R substitution, thereby controlling calcium permeability[10]
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