Identification of tRNA-derived ncRNAs in TCGA and NCI-60 panel cell lines and development of the public database tRFexplorer.

Alessandro La Ferlita,Dario Veneziano,Giovanni Nigita,Veronica Balatti,Carlo M Croce,Salvatore Alaimo,Alfredo Ferro,Alfredo Pulvirenti

doi:10.1093/database/baz115

Alessandro La Ferlita, Dario Veneziano + Show 6 more

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https://doi.org/10.1093/database/baz115

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Abstract

Next-generation sequencing is increasing our understanding and knowledge of non-coding RNAs (ncRNAs), elucidating their roles in molecular mechanisms and processes such as cell growth and development. Within such a class, tRNA-derived ncRNAs have been recently associated with gene expression regulation in cancer progression. In this paper, we characterize, for the first time, tRNA-derived ncRNAs in NCI-60. Furthermore, we assess their expression profile in The Cancer Genome Atlas (TCGA). Our comprehensive analysis allowed us to report 322 distinct tRNA-derived ncRNAs in NCI-60, categorized in tRNA-derived fragments (11 tRF-5s, 55 tRF-3s), tRNA-derived small RNAs (107 tsRNAs) and tRNA 5′ leader RNAs (149 sequences identified). In TCGA, we were able to identify 232 distinct tRNA-derived ncRNAs categorized in 53 tRF-5s, 58 tRF-3s, 63 tsRNAs and 58 5′ leader RNAs. This latter group represents an additional evidence of tRNA-derived ncRNAs originating from the 5′ leader region of precursor tRNA. We developed a public database, tRFexplorer, which provides users with the expression profile of each tRNA-derived ncRNAs in every cell line in NCI-60 as well as for each TCGA tumor type. Moreover, the system allows us to perform differential expression analyses of such fragments in TCGA, as well as correlation analyses of tRNA-derived ncRNAs expression in TCGA and NCI-60 with gene and miRNA expression in TCGA samples, in association with all omics and compound activities data available on CellMiner. Hence, the tool provides an important opportunity to investigate their potential biological roles in absence of any direct experimental evidence.Database URL: https://trfexplorer.cloud/

Highlights

With the advent of next-generation sequencing technologies, the number of characterized non-coding RNAs (ncRNAs) classes in eukaryotic cells has dramatically increased [1–3]
A number of tsRNAs, 5 leader RNAs and tRFs identified across NCI-60 cell lines and The Cancer Genome Atlas (TCGA) samples present noticeable expression levels
All small RNA sequences mapped within four specific regions: 5 end and 3 end of mature tRNA, and 3 trailer and 5 leader (5 leader RNAs) regions of primary tRNA genes

Summary

Introduction

With the advent of next-generation sequencing technologies, the number of characterized ncRNA classes in eukaryotic cells has dramatically increased [1–3]. TRNA-derived non-coding RNAs (ncRNAs), a novel heterogeneous class of ncRNAs originating from tRNA processing, have been characterized. It has been shown that tRNA-derived ncRNAs are not mere byproducts of random tRNA cleavage, rather they may actively play roles in several biological phenomena, such as ribosome biogenesis, retrotransposition, virus infections, apoptosis and cancer pathogenesis [4–13]. Some classes of tRNA-derived ncRNAs have been shown to bind AGO and PIWI proteins, potentially acting as post- or pre-transcriptional regulators of gene expression [9, 14]. TRNA biogenesis begins with the transcription of tRNA genes by RNA polymerase III leading to ‘precursor tRNA’ (pre-tRNA). Such molecules undergo a maturation process inside the nucleus, where 5 leader and 3 trailer sequences are cleaved by ribonuclease P (RNase P) and ribonuclease Z (RNase Z), respectively [15, 20–25]. A common grouping of such molecules is based on the location they originate from within the tRNA gene. tRNA-derived ncRNAs can, be divided into two main classes: (i) tsRNAs, which derive from pretRNA and (ii) stress-induced tRNA fragments (tiRNAs), together with tRFs, which derive from mature tRNA [13]

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