Profiles of miRNA Isoforms and tRNA Fragments in Prostate Cancer

Magee, Rogan; Telonis, Aristeidis G.; Loher, Phillipe; Londin, Eric; Rigoutsos, Isidore

doi:10.1038/s41598-018-22488-2

Cited by 61 publications

(68 citation statements)

References 57 publications

(73 reference statements)

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“…Previously, we showed that tRFs have links to precision medicine and hold promise for furthering our understanding of homeostasis and disease. Specifically, we demonstrated that the identity and abundance of tRFs depend on a person's sex, population origin, and race/ethnicity, as well as tissue, tissue state, and disease type (5,8,19). We also found that the associations ("wiring") of tRFs with mRNAs and molecular pathways is race/ethnicity-specific in prostate adenocarcinoma (8) and triple-negative breast cancer (19).…”

Section: Introductionmentioning

confidence: 78%

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tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities

et al. 2019

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tRNA-derived fragments (tRF) are a class of potent regulatory RNAs. We mined the datasets from The Cancer Genome Atlas (TCGA) representing 32 cancer types with a deterministic and exhaustive pipeline for tRNA fragments. We found that mitochondrial tRNAs contribute disproportionally more tRFs than nuclear tRNAs. Through integrative analyses, we uncovered a multitude of statistically significant and contextdependent associations between the identified tRFs and mRNAs. In many of the 32 cancer types, these associations involve mRNAs from developmental processes, receptor tyrosine kinase signaling, the proteasome, and metabolic pathways that include glycolysis, oxidative phosphorylation, and ATP synthesis. Even though the pathways are common to multiple cancers, the association of specific mRNAs with tRFs depends on and differs from cancer to cancer. The associations between tRFs and mRNAs extend to genomic properties as well; specifically, tRFs are positively correlated with shorter genes that have a higher density in repeats, such as ALUs, MIRs, and ERVLs. Conversely, tRFs are negatively correlated with longer genes that have a lower repeat density, suggesting a possible dichotomy between cell proliferation and differentiation. Analyses of bladder, lung, and kidney cancer data indicate that the tRF-mRNA wiring can also depend on a patient's sex. Sex-dependent associations involve cyclindependent kinases in bladder cancer, the MAPK signaling pathway in lung cancer, and purine metabolism in kidney cancer. Taken together, these findings suggest diverse and wide-ranging roles for tRFs and highlight the extensive interconnections of tRFs with key cellular processes and human genomic architecture.Significance: Across 32 TCGA cancer contexts, nuclear and mitochondrial tRNA fragments exhibit associations with mRNAs that belong to concrete pathways, encode proteins with particular destinations, have a biased repeat content, and are sex dependent.

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Section: Introductionmentioning

confidence: 78%

“…The production of tRFs changes in response to factors like diet variations (6) and trauma (7). It has also been shown that tRFs are produced in a tissue-dependent manner (5), exhibit differential abundances in cancer compared to normal tissue (8,9), and are involved in transgenerational inheritance (10).…”

Section: Introductionmentioning

confidence: 99%

tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities

et al. 2019

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“…However, it has already been shown that, in humans, these endpoint variations are constitutive in both healthy individuals and patients [10,24,25]. In fact, isomiRs have been shown to depend on a person's sex, population origin, and ethnicity [10,24], as well as on tissue, tissue state, and disease subtype [26,27]. Nontemplated nucleotide additions at the 3'-end can be due to nucleotide transferases (TUTase) that generally add adenine or uridine nucleotides [28].…”

Section: Resultsmentioning

confidence: 99%

Unification of miRNA and isomiR research: the mirGFF3 format and the mirtop API

Desvignes

Loher

Eilbeck

et al. 2018

Preprint

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Background:MicroRNAs (miRNAs) are small RNA molecules (~22 nucleotide long) involved in posttranscriptional gene regulation. Advances in high-throughput sequencing technologies led to the discovery of isomiRs, which are miRNA sequence variants. While many miRNA-seq analysis tools exist, a lack of consensus on miRNA/isomiR analyses exists, and the resulting diversity of output formats hinders accurate comparisons between tools and precludes data sharing and the development of common downstream analysis methods. Conclusions:Collectively a comprehensive isomiR categorization system, along with the accompanying mirGFF3 and mirtop API provide a complete solution for the standardization of miRNA and isomiR analysis, enabling data sharing, reporting, comparative analyses, and benchmarking, while promoting the development of common miRNA methods focusing on downstream steps to miRNA detection, annotation, and quantification.

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“…miRDeep2 scores a miRNA by considering the hairpin folding, the mature, star and loop sequence from the hairpin, and the proportion of nucleotides in the mature miRNA passing the RNA folding threshold from the randfold software (Bonnet et al 2004; Lorenz et al 2011) (Github: ebOO/randfold). If multiple sequences reached the same highest miRDeep2 score, the consensus sequence was the sequence with the highest frequency across all libraries. If multiple sequences reached the same highest frequency, the consensus sequence was the longest sequence. If multiple sequences reached the same longest length, the consensus sequence was the collapsed sequence from the stack (this only applies to mature and star sequences). The consensus miRNA genomic coordinates and miRNA sequences were considered as “clean” miRNAs and were retained for analysis. Note, the observation that a stack of reads aligning to the same known precursor, mature or star miRNA varied in length in this lactating dairy cow, is similar to the miRNA isoforms that were detected in healthy humans, where depending on gender, population and race, precursor miRNAs gave rise to many isoforms that typically differed in either 5’ or 3’ termini or both, and the most abundant isoform was frequently annotated as the canonical sequence in miRBase (Telonis et al 2015; Magee et al 2018). However, miRNA isoform was out of the scope of this study, and our method to obtain consensus sequence didn’t consider miRNA isoforms.…”

Section: Methodsmentioning

confidence: 71%

Genome-wide profiling of microRNAs and prediction of mRNA targets in 17 bovine tissues

Prowse-Wilkins

et al. 2019

Preprint

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MicroRNAs regulate many eukaryotic biological processes in a temporal- and spatial-specific manner. Yet in cattle it is not fully known which microRNAs are expressed in each tissue, which genes they regulate, or which sites a given microRNA bind to within messenger RNAs. An improved annotation of tissue-specific microRNA network may in the future assist with the identification of causal variants affecting complex traits. Here, we report findings from analysing short RNA sequence from 17 tissues from a single lactating dairy cow. Using miRDeep2, we identified 699 expressed mature microRNA sequences. Using TargetScan, known (60%) and novel (40%) microRNAs were predicted to interact with 780,481 sites in bovine messenger RNAs homologous with human. Putative interactions between microRNA families and targets were significantly enriched for interactions from previous experimental and computational identification. Characterizing features of microRNAs and targets, we showed that (1) mature microRNAs derived from different arms of the same precursor targeted different genes in different tissues; (2) miRNA target sites preferentially occurred within gene regions marked with active histone modification; (3) variants within microRNAs and targets had lower allele frequencies than variants across the genome, as identified from 65 million whole genome sequence variants; (4) no significant correlation was found between the abundance of microRNAs and messenger RNAs differentially expressed in the same tissue; (5) microRNAs and target sites weren’t significantly associated with allelic imbalance of gene targets. This study contributes to the goals of Functional Annotation of Animal Genomes consortium to improve the annotation of genomes of domestic animals.

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Profiles of miRNA Isoforms and tRNA Fragments in Prostate Cancer

Cited by 61 publications

References 57 publications

tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities

tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities

Unification of miRNA and isomiR research: the mirGFF3 format and the mirtop API

Genome-wide profiling of microRNAs and prediction of mRNA targets in 17 bovine tissues

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