Genomic Identification of RNA Editing Through Integrating Omics Datasets and the Clinical Relevance in Hepatocellular Carcinoma

Abstract

RNA editing is a widespread post-transcriptional mechanism to introduce single nucleotide changes to RNA in human cancers. Here, we characterized the global RNA editing profiles of 373 hepatocellular carcinoma (HCC) and 50 adjacent normal liver samples from The Cancer Genome Atlas (TCGA) and revealed that most editing events tend to occur in minor percentage of samples with moderate editing degrees (20-30%). Moreover, these RNA editing prefer to be A-to-I RNA editing in protein coding genes, especially in 3 ′ UTR regions. Considering the association between DNA mutation and RNA editing, our analysis found that RNA editing maybe a complementary event for DNA mutation of HCC risk genes in HCC patients. We next identified 454 HCC-related editing sites, and many locate on the same genes with the same editing patterns. The functional consequences of editing revealed 2,086 functional editing sites and demonstrated that most editing in coding regions are non-synonymous variations. Furthermore, our results showed that editing in the 3 ′ UTR regions tend to influence miRNA-target binding, and the editing degree seems to be negatively correlated with gene expression. Finally, we found that 46 HCC-related editing sites with consequence are able to distinguish the prognosis differences of HCC patients, suggesting their clinical relevance. Together, our results highlight RNA editing as a valuable molecular resource for investigating HCC mechanisms and clinical treatments.

Global RNA editing identification and characterization during human pluripotent-to-cardiomyocyte differentiation

“…9 Taking this into consideration, the 2 known RNA editing types (A-to-I and C-to-U) together accounted for most of the RNA variants during cardiomyocyte differentiation (Table S1), which is consistent with other studies, and A-to-I editing sites showed a disproportionately high percentage. 9,29 In particular, we also confirmed that approximately 79% of the identified A-to-I editing sites have been found in previous studies stored in the RADAR database. These results collectively indicate that the RNA editing sites identified here are credible.…”

“…Interestingly, for these approximately 70% gene-shared stage-specific editing sites, we found that they tended to be identified in the same differentiation stages (88.33%, 477/540) with a few exceptions that were identified in different stages (11.67%, 63/540; Figure 5 C; Table 3 ), which is similar to the phenomenon observed in hepatocellular carcinoma. 29 Among these stage-specific and stage-shared editing sites, 171 had at least 1 functional consequence, such as amino acid sequence changes, alternative splicing variations, miRNA-target regulation, and gene expression alterations, as shown in Figure 4 . 11 Ud-specific editing sites were located in regions of NANOG ( Table 3 ), of which 6 have a potential effect on miRNA-target changes and expression changes in NANOG ( Figure 4 A).…”

“…The effect of RNA editing on amino acid sequences, alternative splicing, miRNA-target regulation, and gene expression during human cardiomyocyte differentiation RNA editing is similar to DNA mutation and can lead to a series of functional consequences, such as amino acid sequence changes, alternative splicing variations, and RNA regulation alterations, which have been investigated in human diseases. 29 However, the functional effect of RNA editing in the cardiomyocyte differentiation stage has not yet been clarified. Here, we revealed that 43, 163, 544, and 141 editing sites may lead to amino acid sequence changes, alternative splicing variations, miRNA-target regulation, and gene expression alterations, respectively (Figure 4A).…”

An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks

“…The magnitude and the biological consequences of A-to-I editing in the majority of cancers remain largely unknown. Advances in high-throughput sequencing and data generation have revealed that RNA editing events are extensive across the human cancer transcriptome, and that the incidence and progression of multiple cancers are associated with some of these events [7,8,[39][40][41]. In the present study, we aimed to assess the impact of RNA editing in thyroid cancer and to identify de novo cancer-related RNA editing sites using next generation sequencing in an ADAR1-knockdown cellular model.…”

Epitranscriptomics: A New Layer of microRNA Regulation in Cancer

“…Besides these examples on specific miRNAs, a global analysis of miRNA sequencing data from healthy and cancerous tissues unveiled that miRNA editing is frequently dysregulated in cancer [130,[135][136][137][138][139].…”