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

Abstract

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.

Ribosomal RNA fragmentation into short RNAs (rRFs) is modulated in a sex- and population of origin-specific manner

“…At the same time, and in addition to the full-length rRNAs, the nuclear genome is riddled with numerous partial copies of rRNAs. This is in parallel to what we observed for tRFs [26,30,31,48]. However, unlike tRFs, the partial copies of the longer rRNAs such as 12S, 16S, 18S, and 28S that can be found on the genome are themselves long.…”

“…6). This tissue-dependence observation is something that we showed to be the case through two large-scale analyses of isomiRs [25] and tRFs [30]. And, a recent report in bioRχiv [53] showed evidence that the aggregate production of rRFs from the 5′-end of 28S differs across several tissues.…”

“…Moreover, we showed that a person's race, population origin, and sex modulate the clouds of isomiRs in health [23] and disease [24] and do so in a tissue-specific manner [25]. In complete analogy to the isomiRs, we also showed that the clouds of tRFs are also produced constitutively in human tissues, in health [26,27] and disease [28][29][30][31], and are modulated by a person's race, sex, and population origin, as well as by tissue type and tissue state, in health and disease [26,[28][29][30][31].…”

“…We find that the rRFs can arise from any portion of the parental rRNA's span. To be consistent with the notation that is used for tRFs [26][27][28][29][30][31]36], we refer to those rRFs that arise from the 5′-end of an rRNA as "5′-rRFs," those that arise from the interior of an rRNA as "i-rRFs," those that arise from the 3′end of an rRNA as "3′-rRFs," and those that straddle the 5′-or 3′-ends of an rRNA as "x-rRFs." The sequences of the 16,279 rRFs that survive the stringent thresholds (Threshold-seq, ≥ 10 RPM, length cutoffs) are listed in Additional file 4.…”

Translational efficiency across healthy and tumor tissues is proliferation‐related

“…ª 2020 The Authors Molecular Systems Biology 16: e9275 | 2020 knowledge on the underlying mechanisms controlling tRNA expression, degradation, and the effect of their modifications will be further expanded (Pan, 2018;Rak et al, 2018). Recent studies in TCGA have actually observed an upregulation of tRNA-modifying enzymes, as well as proposed a link of tRNA-derived fragments (tRF) to proliferation (Zhang et al, 2018;Telonis et al, 2019). Overall, this is the first high-throughput study of codonanticodon translational efficiency over thousands of samples comprising multiple tissues and disease.…”