Next Article in Journal
The Functional Roles and Regulation of Circular RNAs during Cellular Stresses
Previous Article in Journal
LncRNA-Dependent Mechanisms of Transforming Growth Factor-β: From Tissue Fibrosis to Cancer Progression
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
ncRNA
Volume 8
Issue 3
10.3390/ncrna8030037
ncrna-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

tiRNAs: Insights into Their Biogenesis, Functions, and Future Applications in Livestock Research

by
Fabio Sarais
1,
Alvaro Perdomo-Sabogal
1,
Klaus Wimmers
1,2 and
Siriluck Ponsuksili
1,*
1
Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
2
Faculty of Agricultural and Environmental Sciences, University Rostock, 18059 Rostock, Germany
*
Author to whom correspondence should be addressed.
Non-Coding RNA 2022, 8(3), 37; https://doi.org/10.3390/ncrna8030037
Submission received: 4 May 2022 / Revised: 20 May 2022 / Accepted: 23 May 2022 / Published: 26 May 2022
Browse Figures
Versions Notes

Abstract

:
Transfer RNA (tRNA)-derived small RNAs (tsRNAs) belong to a group of transfer ribonucleic acid (tRNA)-derived fragments that have recently gained interest as molecules with specific biological functions. Their involvement in the regulation of physiological processes and pathological phenotypes suggests molecular roles similar to those of miRNAs. tsRNA biogenesis under specific physiological conditions will offer new perspectives in understanding diseases, and may provide new sources for biological marker design to determine and monitor the health status of farm animals. In this review, we focus on the latest discoveries about tsRNAs and give special attention to molecules initially thought to be mainly associated with tRNA-derived stress-induced RNAs (tiRNAs). We present an outline of their biological functions, offer a collection of useful databases, and discuss future research perspectives and applications in livestock basic and applied research.

Graphical Abstract

1. Introduction

Genome conservation of nucleotides located outside the exons of protein-coding genes increases with the complexity of the organisms across different phyla [1,2,3]. An organism’s complexity seems more related to the quantity of non-coding RNA genes (ncRNAs) than to the number of protein-coding genes [4].
Non-coding RNAs can be divided into two main groups depending on their transcription length: small ncRNAs (sncRNAs) and long ncRNAs (lncRNAs) [5,6]. Small ncRNAs are characterised by a diverse list of recently found RNA species, many of which are linked to the 5′ or 3′ regions of protein-coding genes. This class comprises micro RNAs (miRNAs), small interfering RNAs (siRNAs), piwi-interacting RNAs (piRNAs), small nuclear RNA (snRNAs), small nucleolar RNA (snoRNAs), centromere repeat-associated small interacting RNAs (crasiRNA), telomere-specific small RNAs (tel-sRNAs), tRNA-derived small RNA, Pyknons, tRFs, and tiRNAs (Table 1). The pervasive transcription detected in mammalian genomes, together with the numerous processes leading to the regulation of ncRNA expression, posit a universe of ncRNA in which their specific biological roles are yet to be explored [7,8].
Among all ncRNAs, tRNAs play essential roles in transporting amino acids into the ribosomes to facilitate mRNA coordinated protein biosynthesis. tRNAs are a group of RNAs well-known for their cloverleaf secondary structure and L-shaped tertiary structure. Specific enzymes, exonucleases, can selectively break tRNAs into several small fragments during biogenesis. This cleavage results in two major classes of tRNA-derived fragments tRFs and tRNA halves (tsRNAs) (Table 1). The biological importance of these short RNAs is yet to be determined [18]. tRNA cleavage products exert similar effects to miRNA [19]; for instance, tRNAGlyGCC showed functional similarities to miRNAs in B-cells lymphoma, specifically interacting with Argonaute (AGO) proteins and downregulating mRNA transcription [20]. Different tRNA fragments, including tRNA-derived stress-induced RNA (tiRNA), have been recently associated with multiple cellular and molecular mechanisms associated with stress responses and diseases such as immune and metabolic disorders, and cancer [18,21,22,23]. This highlights the relevance of deciphering their biogenesis, the effect of exonucleases on their production, and their biological role.

2. tiRNA Classification, Biogenesis, and Subcellular Localisation

During their entire lifecycle, tRNAs go through substantial processing that involves a variety of chemical changes [24]. RNA polymerase activity transcribes tRNAs into precursor tRNAs (pre-tRNAs) [25]. Then, the nuclear localised endonucleases Z (RNase Z) together with RNase P cleave the 3′-trailer and 5′-leader sequences from pre-tRNA during tRNA maturation, releasing a 1-tRF characterised by a polyuridine tail [26]. Subsequently, the mature tRNA can be precisely cleaved, mainly by angiogenin, but also from other specific riboexonucleases such as Dicer, generating different structural types (Figure 1). While Dicer is a cytosolic protein, angiogenin is a nuclear protein that translocates and accumulates in the cytoplasm.
Based on the relationship to their parental tRNA sequence, these structural types are classified into six groups as follows. Groups (i) 5-tRF and (ii) 3-tRF, are 14–30 nt in length, and they derive from mature or precursor tRNAs. Groups (iii) 5′-tiRNA commonly known as 5′-tRNA halves and (iv) 3′-tiRNA well-known as 3′-tRNA halves, are 29–50 nt in length, and their generation is induced by stress. The group (v) i-tRFs are ~36 nt in length, it derives from internal parts of tRNAs. Finally, the group (vi) tRF-2, recently discovered tRFs, which carry anticodon stem and loop regions of mature tRNAs [27,28] (Figure 1). It has already been documented that groups i to iv are mainly processed by angiogenin and Dicer [29].
Importantly, Telonis et al. highlighted that the length of various tsRNAs may be tissue-type and tissue-state specific [30]. Moreover, previous studies observed that the distribution of length of tsRNAs revealed that tRNAs with a high percentage of G:C pairs in the T stem produce, by far, more 5′-tRNA fragments than 3′-tRNA fragments. Conversely, tRNAs with 100% G:C pairs in the D stem mainly produced 3′-tRNA fragments. This suggests that tRNA fragment abundance is related to its sequence G:C composition and secondary structure [31]. Further studies showed that the stability and the abundance of certain tRNA fragments can be impacted by sequence modifications [32,33].
In 1990, Levitz et al. [34] reported for the first time, the cleavage of tRNA upon phage-T4 infection. The first fundamental evidence indicating the regulatory properties of tRNAs on human urinary bladder carcinoma was reported about 10 years later [35]. Ten years later, Yamasaki et al. and Fu et al. discovered the role of angiogenin on tRNAs fragment generation [36,37]. Initially, it was thought that most of tsRNAs were found in the cytoplasm [38], where exonucleases such as Dicer and angiogenin can specifically cleave the tRNAs into tRFs [34] and tiRNAs [39]. However, tsRNAs have been recently detected in the serum of small extracellular vesicles of humans, rats, and mice. Notably, mice and rats display a large abundance of tRNA-derived noncoding RNAs as well as miRNAs [40]. Similarly, tRNA-encoding genes have been found in mitochondria across different taxa (n = 22) [41]. Specific cleavage of these mt-tRNAs generates mt-tsRNAs that differ in sequence and length from nuclear tsRNAs [42]. Although the cleavage and transport of the mt-tRNAs remain yet to be experimentally validated, two mechanisms have been proposed. In the first one, mt-tRNAs are transported out of the mitochondria into the cytoplasm, and subsequently processed by Dicer and AGO2 proteins. In the second one, mitochondrial localised Dicer and AGO2 process the mt-tRNAs into mt-tsRNAs, and then these are transported into the cytoplasm. Once in the cytoplasm, these mt-tRNAs may take part in the regulation of nuclear-encoded genes [43,44]. The mt-tsRNAs have been recognised in cardiac tissue, where they play a crucial function in mitochondrial protein translation [28]. Importantly, non-mt-tRNAs can also be imported into the mitochondria, which suggests they may also play important roles in mitochondrial gene regulation [45].

3. Regulation of tiRNA Processing by Angiogenin

Angiogenin gene (ANG), also known as RNase5, encodes for a 14.4 kDa protein that is specific to vertebrates (Table 2). This gene acts as a neovascularisation enhancer [46] and it is also involved in pathologies such as cancer and neurodegeneration [47,48].
The specific cleavage activity on tRNAs suggests that angiogenin-induced tRNA cleavage occurs during stressful events such as starvation, hypoxia, and hypothermia [36,37]. Similar conserved mechanisms determining cell survival and damage [53] have been reported in S. cerevisiae, where yeast protein (Rny1p), an RNase component of a different family than angiogenin, generates tRNA cleavage upon oxidative stress. Under homeostatic conditions, angiogenin is retained in the nucleus, where it is held in a latent form by its direct inhibitor RNH1 (RNase inhibitor 1) [54]. Upon stress stimuli, angiogenin dissociates from RHN1, probably caused by post-transcriptional modifications mainly asserted by protein kinase C (PKC and cyclin-dependent kinases (CDKs), which phosphorylate angiogenin serine residues and reduce the affinity for its inhibitor, enabling angiogenin–exonuclease activity and promoting tRNAs’ cleavage [55]. RNH1 suppresses angiogenin activity by binding to its catalytic domain of Lys-40, His-13, and His-11 [55]. While ANG expression is mainly carried out in the liver, RNH1 is expressed in endothelial cells as well as in neurons, glial cells, erythroid cells, and osteoblasts, among other cell types.
An important regulator of ANG expression is the transcription factor (TF) HIF-1α siRNA-mediated knockdown of the HIF-1α gene revealed that HIF-1α is likely to bind the promoter region of the ANG gene and downregulate its expression [56]. Similar studies have also shown that ANG overexpression in HEK293T and U2OS cell lines results in the upregulation of 5′-tiRNAs (up to 5.7-fold) and 3′-tiRNAs (up to 11-fold) [57], with specifically enhanced production of 5′-tiRNAs of 31–36 nt and 3′-tiRNAs of 36–41 nt in length [57]. Interestingly, overexpression of ANG also results in the up-regulation of miRNAs and down-regulation of tRNA-derivated piRNAs (td-piRNAs) expression, showing the involvement of angiogenin in the biogenesis of other sncRNAs [57].
Specific types of tRNAs, such as tRNAGlu, tRNAGly, tRNALys, tRNAVal, tRNAHis, tRNAAsp, and tRNASeC, are more sensitive to cleavage by angiogenin activity [37,57,58]. The preference for angiogenin cleavage seems to be associated with either the selectivity of riboexonuclease to certain substrates, [57,59] or increased stability of specificity for tRNA species [60]. While the selectivity may be influenced by sequence and tRNA modifications [59,61] (Figure 2b), 5′-tiRNA derived from tRNAGly and tRNAGlu revealed dimerization processes that may confer higher stability [60]. CRISPR-Cas9-mediated Knock-out of the ANG gene in HEK293T and U2OS cell lines showed that only specific tiRNA are affected, whereas most of the tiRNAs were produced via angiogenin-independent processes [57]. This suggests that aside from angiogenin, there are other RNases able to process the cleavage of tiRNAs. For instance, RNase A, a ribonuclease from vertebrates, despite the stress-induced cleavage of tRNAs, is a highly conserved mechanism in bacteria and plants [53,62,63]. Further evidence of independent angiogenin cleavage mechanisms is provided by several studies describing other RNases’ activities [64], such as RNase L [65], RNase 1 [66], Schlafen13/SFLN13 [67], and Dicer [68] (Figure 2a).

4. Role of tiRNA in Development, Cell Differentiation, and Apoptosis

While there is abundant information about the role of specific subsets of sncRNAs, such as miRNAs, piRNAs, and siRNAs, in development and cell differentiation, the role of tiRNAs is still poorly understood [69]. Previous studies have shown evidence of the regulatory roles of sncRNAs during cell differentiation. During development, sncRNAs are also expressed in tissue and cell-specific ways suggesting that they play a role in protein expression by interacting with promoter regions and modulating gene expression, for instance, in neurons, muscle, and germ cells [70]. Previous studies showed that several instances of differential tRNA gene expression resulted in changes in the abundance of tRNA-derived fragments but not of mature tRNAs. This shows that noncanonical tRNA activities can be modulated by selectively expressing tRNA genes without harming the mature tRNA pool. This process may be critical for the control of tiRNA functions at the tissue level [71]. It has also been demonstrated that specific sets of 5′-tiRNAs, such as derived from tRNAGlyGCC, tRNAValCAC, tRNAGlnCTG, tRNAGluTTC, and tRNALysTTT, have an important roles during development [69]. These specific sets of 5′-tiRNAs are able to interact with a selected group of proteins and transcripts during mouse embryonic stem cells (mESCs) differentiation. For example, they interact with Igf2bp1, an RNA-binding protein that regulates the expression and translation of c-Myc, an important TF proto-oncogene in cell differentiation and transformation [69,72]. Further studies on hematopoietic stem cells identified the role of the Pseudouridine Synthase 7 (PUS7) on protein synthesis and cell growth. PUS7 mediates the pseudouridylation and it is an important enzyme for epigenetic modification [73]. Downregulation of PUS7 disrupts tRNA-derived fragment-mediated translation control in embryonic stem cells, specifically 5′-tiRNAs derived from tRNAs harbouring a 5′ terminal oligoguanine (TOG), such as tRNAAla, tRNACys, or tRNAVal. This disruption results in increased protein production and faulty germ layer determination [74]. Moreover, 5′-tiRNAAla and 5′-tiRNACys harbouring a terminal TOG motif, inhibit translation by establishing an intermolecular RNA G-quadruplexes (RG4), replacing the translational initiation complex eIF4G/eIF4E on the mRNA cap (m7GTP) structure [18,75,76] (Figure 3).
tiRNAs seem to also play important roles in aging and spermatogenesis. The aging process comprises several physiological processes that have been summarised in eight hallmarks: loss of proteostasis, stem cell exhaustion, altered intercellular communication, deregulated nutrient sensing, cellular senescence, telomere attrition, mitochondrial dysfunction, genomic instability, and epigenetic alteration [77]. According to studies in human and model species, tiRNAs, and more generally tsRNAs, exhibit diverse expression patterns in the settings of age-related illnesses and physiological senescence.
It has been observed that the composition quantity of circulating 5′-tiRNAs changes during the normal aging process, with a decrease mainly in tRNACysGCA and tRNALysCTT-derived 5′-tiRNAs, and an increase in tRNAHisGTG and tRNAAspGTC in mice [78]. Other tiRNAs have also been detected as differentially expressed during aging (Table 3), which suggests their putative role in the process.
Of note, 5′-tiRNAs are the predominant tsRNA fragments in motile spermatozoa of several mammals, raising the hypothesis of an active role during late-stage spermatogenesis and zygotic programming [84,85,86]. The high concentration of 5′-tiRNA in mammalian motile sperm is regulated by tRNA methyltransferase 2 (DNMT2), which primarily catalyses the methylation of tRNAs to yield 5′-methylcytosine (m5C) modification [33,87]. Similarly, 3′-tiRNAs have also been identified in human sperm, but are not as abundant as 5′-tiRNAs [84,88]. In addition, the interaction of tiRNAs with PIWI, a family of proteins involved in germ cell maintenance and gamete differentiation [89], suggests their important role in mammalian reproduction and development. For instance, tRNAValCAC halves retrieved in gonads and kidneys of non-stressed animals interact with the PIWIL4 protein, into a PIWIL4-piRNA complex, which putatively works as translation initiation and efficiency factors [90].
Apoptosis is another key developmental process controlled by specific gene expression, where two signalling cascades come together to activate a set of effector caspases, caspase 3 and 7. The activation of the apoptotic process leads to the release of Cyt-C, which associates with Apaf-1 and activates the two effector caspases resulting in apoptotic degradation [91]. tiRNAs interaction with Cyt-C to form the RNPs complex has also been associated with the regulation of apoptosis during osmotic stress [92]. Therefore, these ANG-derived tiRNAs are key for inhibiting the formation of the apoptosome [92].

5. Role of tiRNA on Immunity and Their Potential as Cross-Species Biomarkers

tiRNAs have been recognised as potential systemic immune signalling molecules [93]. 5′-tiRNAs circulate in the bloodstream and may work as extracellular miRNAs in response to viral infections and immune reactions [94]. These tiRNAs may induce the independent assembly of stress-related granules, translating messenger ribonucleoproteins (mRNPs) that can temporarily silence mRNAs, thus helping cells to survive. However, unlike circulating miRNAs released in all peripheral tissues, circulating 5′-tiRNAs appear to be localised mainly in haematological and lymphoid tissues, thus suggesting their function in the immune system [80].
The roles of tiRNAs in relevant pathways such as NF-κB, IFN, and Wnt/β-Catenin also suggest their role in immune responses [95]. For instance, the activation of Toll-like receptor 4 (TLR-4) with bacterial lipopolysaccharides (LPS) induces a signalling cascade that enhances NF-κB activation and promotes the expression of ANG exonuclease. Cytosolic angiogenin mediates the cleavage of 5′-tiRNAs that are released as signalling molecules after being selectively packed into extracellular vesicles (EVs). The complex EV-5′-tiRNA is then transported into endosomes in recipient cells, activating the TLR-7, and enhancing the expression of immune-related genes (Figure 4) [96]. Although the selection mechanism of specific tiRNAs is yet unknown, discriminatory EV integration of miRNAs and tRFs has also been demonstrated [97,98,99].
Interferon expression is regulated by JAK/STAT pathway activation. Upon viral infection, interferons are secreted and reduce the expression of the ANG gene [100].
Downregulation of ANG alters the biogenesis of tiRNAs, changing it into an antiviral state-specific tiRNAs production. The biogenesis of this specific pool of tiRNAs has been proposed to be dependent on other RNases, such as those from the Schlafen family, recently described for their ability to degrade the 3′ end to generate complete 5′ fragments [67]. Another example is 5′-tiRNAVal, which is able to directly bind the human Frizzled homolog 3 (FZD3) and mediate the downregulation of one of the most critical factors of the Wnt signalling pathway. This mediation controls the formation of effector T cells, the activation of regulatory T cells, and the maturation of dendritic cells (Figure 5) [81,101]. In addition, the genomic localisation of the largest tRNA cluster in humans and other mammals, suggests an important relationship between the immune system and tiRNAs. In humans, the largest tRNA gene cluster is localised in the major histocompatibility complex (MHC) [102].
Bearing in mind that tiRNAs fragments have a role in a variety of gene regulatory mechanisms and influence pathways that are linked to animal features that are economically relevant, they represent possible biomarkers of relevance for detecting and understanding infectious illnesses in farm animal species [103]. In the last few years, the characterisation of sncRNAs in food for humans has triggered several studies in the field of nutrigenomics. For instance, milk includes tiRNAs and tRFs that are encapsulated inside EVs, making them resistant to digestion and potentially absorbable by humans [104]. Because of their great conservation, tsRNAs might be used to mediate cross-species gene expression control, which could have a wide spectrum of uses in the context of human nutrition. Meat quality is affected by fat content, which is regulated by several genes such as LATS2, which regulates fat metabolism [105]. A specific tRNA half, 5′-tiRNAHisGTG, regulates the expression of LATS2 [106], which may also associate with meat quality. Additionally, differences in tRNA expression profiles have been identified in large offspring syndrome (LOS) in ruminants, which has been identified as a consequence of assisted reproductive technologies (ART) such as in vitro fertilisation and embryo transfers [31]. There are several tiRNA involved in farm animal diseases that may represent a risk for human health as well (Table 4). Taken together, regulation of the sncRNA milk profile by nutrition, both in humans and dairy cattle, livestock rearing practices, feeding technology, as well as the development of new-born formulae are just some examples where the use of tRNA fragments (tiRNAs and tRFs) as biomarkers may have a great impact in animal and human health [107].

6. Role of tiRNAs in Stress Signalling and Behaviour

Stress signalling is a cellular communication system that increases cellular stress response. Stress signalling can either minimise potential harm or cause apoptosis depending on the intensity of the exposure. The c-Jun N-terminal kinases (JNK) and p38 MAPK signalling pathways regulate adaptive responses to intracellular and extracellular stressors, including UV radiation, heat, and hyperosmotic circumstances, as well as inflammatory cytokines stimulation [113]. Stressed cells enhance the expression of ANG, and its translocation into the cytoplasmic compartment, where it cleaves tRNAs at the anticodon loop to generate tiRNAs and promote stress granule biogenesis (Figure 6) [37].
Previous studies have revealed putative regulatory functions of tiRNAs in porcine brain [115]. While expression profiles differences between the limbic and the hypothalamic–pituitary–adrenal (HPA)-axis tissues suggested that the limbic brain (amygdala and hippocampus) displays a remarkably large concentration of 3’-tiRNAs in phenotypes associated with copying behaviour in pigs, the adrenal gland, an important tissue for regulating the HPA-axis responses to stress, lacked unique 3′-/5′-tiRNA profiles [115]. Similarly, tRFs were found exclusively in the brain tissues, and 3′-tiRNAs showed enrichment in the amygdalar–hippocampal complex [115]. Whereas, 5′-tiRNAs were equally expressed in all four tissues (amygdala, hippocampus, adrenal gland, and hypothalamus) [115]. This suggests that tRNA-derived fragments (tiRNAs and tRFs) show a tissue-specific distribution [115].
Specific sets of tiRNAs may be connected to the coping behaviour in pigs. Upon early life stress, the amygdala from a low reactive haplogroup displayed 5′-tiRNA and 5′-tRF (5’-tRFLys, 5’-tiRNALys, 5’-tiRNACys, and 5’-tiRNAGln) enrichments in pigs. Whereas the hypothalamus from the high-reactive haplogroup evidenced an enrichment of 3′-tiRNAs, including 3′-tiRNAGln, 3′-tiRNAAsn, 3′-tiRNAVal, 3′-tiRNACys, and 3′-tiRNAIle. The same study suggests that 5′-tiRNALeu, together with other miRNAs and mRNAs molecules, may have a specific function as a gene regulator and signalling molecules across coping behaviour haplogroups [116]. Comparative transcriptomic studies between primates and other mammals also revealed different expression profiles across species, suggesting that 5′-tiRNAs are more expressed in the hippocampus in primates, pigs, rats, and mice. 5′-tiRNAGluCTC and 5′-tiRNAGlyGCC were the most abundant among all the 5′-tiRNA, which suggest a well-conserved role in primate’s hippocampus neurogenesis [117].

7. tsRNA Databases

The expansion of RNA high-throughput sequencing techniques has improved the continuous discovery of tsRNAs. Various tsRNAs databases have been created to facilitate the access and study of their molecular roles in different physiological processes (Table 4) [118]. tRFdb was the first database of transfer RNA-related fragments. It collects official names, read counts, and sequences of tRNA fragments from eight organisms: R. sphaeroides, S. pombe, D. melanogaster, C. elegans, X. tropicalis, D. rerio, M. musculus, and H. sapiens [119]. The tRFexplorer database allows users to visualise the expression profiles of tRNA-derived ncRNAs in each NCI-60 cell line panel. This enabled the assessment of tRNA-derived ncRNA expression with CellMiner Omics and chemical activity data. Such a step represents a good opportunity to examine their putative biological significance in the lack of experimental validation [120]. The tsRBase database contains tsRNA IDs, sequences, source tRNAs, and expression values for approximately 14,000 samples from 20 different species, including vertebrate and invertebrate, plants, bacteria, and fungi (Figure 7) [121]. Another interactive database is GtRNAdb, a tool that allows exploring gene predictions. GtRNAdb is continuously increasing content wise, and it is the most often cited web-based repository of tRNA gene information (Table 5) [122]. In comparison to tRFdb ID and MINTbase ID, tDRnamer offers a consistent, stable name and extra annotation for each submitted tDR sequence [103]. Other tools, such as tRNA Analysis of eXpression (tRAX) allows the analysis of tRNA-derived small RNAs (tDRs) and mature tRNAs, and the inference of RNA changes from high-throughput small RNA sequencing data [104] (Table 6).

8. Conclusions and Future Perspectives

Since the earliest reports on the non-ribosomal functions of tRNAs, new data have revealed the “non-canonical” functions of tRNAs. The list keeps growing, especially with the expansion of the types and the description of the cellular-specific features of tRNA fragments. These types and features have considerably attracted attention in the last 5 years in areas such as human health and disease, and, also, in physiological responses to stress-related environmental factors. In this review, we describe the physiological mechanisms by which tiRNAs are generated and how they take part in multiple essential physiological regulatory mechanisms and pathways. We also present a collection of useful databases of great use for further exploring tiRNAs.
Despite the emerging interest and the constantly increasing information, many aspects of tiRNAs and generally about tRNA fragments are not clear yet. Unfortunately, tRFs and tiRNA have been lately rediscovered from small non-coding RNA data sets. This was probably due to experimental designs mainly focused on miRNAs where sequences longer than 18–24 nt were routinely deleted, and reads that aligned with tRNAs, rRNAs, or snoRNAs were deemed as degradation products, thus being removed during the quality controls [123].
The new discovery of novel ncRNAs has expanded our knowledge about their tissue-specific expression patterns, diverse interactions, and subcellular locations, something that will surely expand our comprehension of their putative functional regulatory activities, among other physiological roles.
As potential biomarkers, tsRNAs have promising value in the fields of human and animal health. Similar to miRNAs biomarkers [124], tsRNAs may offer additional measures of biological states for stress associated with anthropogenic, environmental (including temperature stress), pathogen, and aging-related factors in humans, but also in farm animal research, as already shown in pigs [125]. The composition, stability, and abundance of tRFs and tiRNAs are highly dependent on cell type and disease state and are highly enriched in biofluids, much more so than microRNAs, making them excellent biomolecules for biomarkers. It is plausible to use the level of tsRNAs as a potential biomarker, by comparing it with conventional biomarkers such as cortisol level. The validation of results in a large number of animals for potential uses as molecular biomarkers in determining the health status of farm animals is necessary.

Author Contributions

Conceptualization, F.S., S.P. and A.P.-S.; methodology, F.S.; software, F.S.; formal analysis, F.S. and A.P.-S.; resources, S.P.; writing—original draft preparation, F.S.; writing—review and editing, S.P., A.P.-S. and K.W.; supervision, S.P.; project administration, S.P.; funding acquisition, S.P. All authors have read and agreed to the published version of the manuscript.

Funding

The cost for the publication of this article was funded by the Open Access Fund of the FBN.

Acknowledgments

We thank Frieder Hadlich for the interesting and helpful discussions.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Vavouri, T.; Walter, K.; Gilks, W.R.; Lehner, B.; Elgar, G. Parallel Evolution of Conserved Non-Coding Elements That Target a Common Set of Developmental Regulatory Genes from Worms to Humans. Genome Biol. 2007, 8, R15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Siepel, A.; Bejerano, G.; Pedersen, J.S.; Hinrichs, A.S.; Hou, M.; Rosenbloom, K.; Clawson, H.; Spieth, J.; Hillier, L.W.; Richards, S.; et al. Evolutionarily Conserved Elements in Vertebrate, Insect, Worm, and Yeast Genomes. Genome Res. 2005, 15, 1034–1050. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Sun, H.; Skogerbø, G.; Chen, R. Conserved Distances between Vertebrate Highly Conserved Elements. Hum. Mol. Genet. 2006, 15, 2911–2922. [Google Scholar] [CrossRef] [Green Version]
  4. Kapusta, A.; Feschotte, C. Volatile Evolution of Long Noncoding RNA Repertoires: Mechanisms and Biological Implications. Trends Genet. 2014, 30, 439–452. [Google Scholar] [CrossRef] [Green Version]
  5. Mattick, J.S. Non-Coding RNAs: The Architects of Eukaryotic Complexity. EMBO Rep. 2001, 2, 986–991. [Google Scholar] [CrossRef]
  6. Sana, J.; Faltejskova, P.; Svoboda, M.; Slaby, O. Novel Classes of Non-Coding RNAs and Cancer. J. Transl. Med. 2012, 10, 103. [Google Scholar] [CrossRef] [Green Version]
  7. Sun, Y.-M.; Chen, Y.-Q. Principles and Innovative Technologies for Decrypting Noncoding RNAs: From Discovery and Functional Prediction to Clinical Application. J. Hematol. Oncol. 2020, 13, 109. [Google Scholar] [CrossRef]
  8. Wang, J.; Samuels, D.C.; Zhao, S.; Xiang, Y.; Zhao, Y.Y.; Guo, Y. Current Research on Non-Coding Ribonucleic Acid (RNA). Genes 2017, 8, 366. [Google Scholar] [CrossRef] [Green Version]
  9. O’Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front. Endocrinol. 2018, 9, 402. [Google Scholar] [CrossRef] [Green Version]
  10. Dana, H.; Chalbatani, G.M.; Mahmoodzadeh, H.; Karimloo, R.; Rezaiean, O.; Moradzadeh, A.; Mehmandoost, N.; Moazzen, F.; Mazraeh, A.; Marmari, V.; et al. Molecular Mechanisms and Biological Functions of SiRNA. Int. J. Biomed. Sci. 2017, 13, 48–57. [Google Scholar]
  11. Lim, R.S.M.; Kai, T. A Piece of the Pi(e): The Diverse Roles of Animal PiRNAs and Their PIWI Partners. Semin. Cell Dev. Biol. 2015, 47–48, 17–31. [Google Scholar] [CrossRef] [PubMed]
  12. Liang, J.; Wen, J.; Huang, Z.; Chen, X.P.; Zhang, B.X.; Chu, L. Small Nucleolar RNAs: Insight into Their Function in Cancer. Front. Oncol. 2019, 9, 587. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Lindsay, J.; Carone, D.M.; Brown, J.; Hall, L.; Qureshi, S.; Mitchell, S.E.; Jannetty, N.; Hannon, G.; Renfree, M.; Pask, A.; et al. Unique Small RNA Signatures Uncovered in the Tammar Wallaby Genome. BMC Genom. 2012, 13, 559. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Cao, F.; Li, X.; Hiew, S.; Brady, H.; Liu, Y.; Dou, Y. Dicer Independent Small RNAs Associate with Telomeric Heterochromatin. RNA 2009, 15, 1274–1281. [Google Scholar] [CrossRef] [Green Version]
  15. Evangelista, A.F.; de Menezes, W.P.; Berardinelli, G.N.; dos Santos, W.; Scapulatempo-Neto, C.; Guimarães, D.P.; Calin, G.A.; Reis, R.M. Pyknon-Containing Transcripts Are Downregulated in Colorectal Cancer Tumors, and Loss of PYK44 Is Associated with Worse Patient Outcome. Front. Genet. 2020, 11, 1212. [Google Scholar] [CrossRef]
  16. Zhu, L.; Ge, J.; Li, T.; Shen, Y.; Guo, J. TRNA-Derived Fragments and TRNA Halves: The New Players in Cancers. Cancer Lett. 2019, 452, 31–37. [Google Scholar] [CrossRef]
  17. Tao, E.W.; Cheng, W.Y.; Li, W.L.; Yu, J.; Gao, Q.Y. TiRNAs: A Novel Class of Small Noncoding RNAs That Helps Cells Respond to Stressors and Plays Roles in Cancer Progression. J. Cell. Physiol. 2020, 235, 683–690. [Google Scholar] [CrossRef]
  18. Liu, B.; Cao, J.; Wang, X.; Guo, C.; Liu, Y.; Wang, T. Deciphering the TRNA-Derived Small RNAs: Origin, Development, and Future. Cell Death Dis. 2021, 13, 24. [Google Scholar] [CrossRef]
  19. Su, Z.; Frost, E.L.; Lammert, C.R.; Przanowska, R.K.; Lukens, J.R.; Dutta, A. TRNA-Derived Fragments and MicroRNAs in the Maternal-Fetal Interface of a Mouse Maternal-Immune-Activation Autism Model. RNA Biol. 2020, 17, 1183–1195. [Google Scholar] [CrossRef]
  20. Maute, R.L.; Schneider, C.; Sumazin, P.; Holmes, A.; Califano, A.; Basso, K.; Dalla-Favera, R. TRNA-Derived MicroRNA Modulates Proliferation and the DNA Damage Response and Is down-Regulated in B Cell Lymphoma. Proc. Natl. Acad. Sci. USA 2013, 110, 1404–1409. [Google Scholar] [CrossRef] [Green Version]
  21. Cammas, A.; Millevoi, S. RNA G-Quadruplexes: Emerging Mechanisms in Disease. Nucleic Acids Res. 2017, 45, 1584–1595. [Google Scholar] [CrossRef] [Green Version]
  22. Gao, Z.W.; Wang, X.; Zhang, H.Z.; Lin, F.; Liu, C.; Dong, K. The Roles of Adenosine Deaminase in Autoimmune Diseases. Autoimmun. Rev. 2021, 20, 102709. [Google Scholar] [CrossRef]
  23. Xu, H.; Chen, W.; Zheng, F.; Tang, D.; Dai, W.; Huang, S.; Zhang, C.; Zeng, J.; Wang, G.; Dai, Y. The Potential Role of TRNAs and Small RNAs Derived from TRNAs in the Occurrence and Development of Systemic Lupus Erythematosus. Biochem. Biophys. Res. Commun. 2020, 527, 561–567. [Google Scholar] [CrossRef]
  24. Hopper, A.K.; Nostramo, R.T. TRNA Processing and Subcellular Trafficking Proteins Multitask in Pathways for Other RNAs. Front. Genet. 2019, 10, 96. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Krahn, N.; Fischer, J.T.; Söll, D. Naturally Occurring TRNAs with Non-Canonical Structures. Front. Microbiol. 2020, 11, 2616. [Google Scholar] [CrossRef]
  26. Phizicky, E.M.; Hopper, A.K. TRNA Biology Charges to the Front. Genes Dev. 2010, 24, 1832–1860. [Google Scholar] [CrossRef] [Green Version]
  27. Yu, M.; Lu, B.; Zhang, J.; Ding, J.; Liu, P.; Lu, Y. TRNA-Derived RNA Fragments in Cancer: Current Status and Future Perspectives. J. Hematol. Oncol. 2020, 13, 121. [Google Scholar] [CrossRef]
  28. Cao, J.; Cowan, D.B.; Wang, D.-Z. TRNA-Derived Small RNAs and Their Potential Roles in Cardiac Hypertrophy. Front. Pharm. 2020, 11, 572941. [Google Scholar] [CrossRef]
  29. Yue, T.; Zhan, X.; Zhang, D.; Jain, R.; Wang, K.W.; Choi, J.H.; Misawa, T.; Su, L.; Quan, J.; Hildebrand, S.; et al. SLFN2 Protection of TRNAs from Stress-Induced Cleavage Is Essential for T Cell–Mediated Immunity. Science 2021, 372, eaba4220. [Google Scholar] [CrossRef]
  30. Telonis, A.G.; Loher, P.; Honda, S.; Jing, Y.; Palazzo, J.; Kirino, Y.; Rigoutsos, I. Dissecting TRNA-Derived Fragment Complexities Using Personalized Transcriptomes Reveals Novel Fragment Classes and Unexpected Dependencies. Oncotarget 2015, 6, 24797–24822. [Google Scholar] [CrossRef] [Green Version]
  31. Chen, L.; Xu, W.; Liu, K.; Jiang, Z.; Han, Y.; Jin, H.; Zhang, L.; Shen, W.; Jia, S.; Sun, Q.; et al. 5′ Half of Specific TRNAs Feeds Back to Promote Corresponding TRNA Gene Transcription in Vertebrate Embryos. Sci. Adv. 2021, 7, eabh0494. [Google Scholar] [CrossRef]
  32. Blanco, S.; Dietmann, S.; Flores, J.V.; Hussain, S.; Kutter, C.; Humphreys, P.; Lukk, M.; Lombard, P.; Treps, L.; Popis, M.; et al. Aberrant Methylation of t RNA s Links Cellular Stress to Neuro-developmental Disorders. EMBO J. 2014, 33, 2020–2039. [Google Scholar] [CrossRef]
  33. Schaefer, M.; Pollex, T.; Hanna, K.; Tuorto, F.; Meusburger, M.; Helm, M.; Lyko, F. RNA Methylation by Dnmt2 Protects Transfer RNAs against Stress-Induced Cleavage. Genes Dev. 2010, 24, 1590–1595. [Google Scholar] [CrossRef] [Green Version]
  34. Levitz, R.; Chapman, D.; Amitsur, M.; Green, R.; Snyder, L.; Kaufmann, G. The Optional E. coli Prr Locus Encodes a Latent Form of Phage T4-Induced Anticodon Nuclease. EMBO J. 1990, 9, 1383–1389. [Google Scholar] [CrossRef]
  35. Zhao, H.; Bojanowski, K.; Ingber, D.E.; Panigrahy, D.; Pepper, M.S.; Montesano, R.; Shing, Y. New Role for TRNA and Its Fragment Purified from Human Urinary Bladder Carcinoma Conditioned Medium: Inhibition of Endothelial Cell Growth. J. Cell. Biochem. 2000, 76, 109–117. [Google Scholar] [CrossRef]
  36. Yamasaki, S.; Ivanov, P.; Hu, G.F.; Anderson, P. Angiogenin Cleaves TRNA and Promotes Stress-Induced Translational Repression. J. Cell Biol. 2009, 185, 35–42. [Google Scholar] [CrossRef] [Green Version]
  37. Fu, H.; Feng, J.; Liu, Q.; Sun, F.; Tie, Y.; Zhu, J.; Xing, R.; Sun, Z.; Zheng, X. Stress Induces TRNA Cleavage by Angiogenin in Mammalian Cells. FEBS Lett. 2009, 583, 437–442. [Google Scholar] [CrossRef] [Green Version]
  38. Sobala, A.; Hutvagner, G. Transfer RNA-Derived Fragments: Origins, Processing, and Functions. Wiley Interdiscip. Rev. RNA 2011, 2, 853–862. [Google Scholar] [CrossRef] [Green Version]
  39. Prehn, J.H.M.; Jirström, E. Angiogenin and TRNA Fragments in Parkinson’s Disease and Neurodegeneration. Acta Pharmacol. Sin. 2020, 41, 442–446. [Google Scholar] [CrossRef]
  40. Zhao, F.; Cheng, L.; Shao, Q.; Chen, Z.; Lv, X.; Li, J.; He, L.; Sun, Y.; Ji, Q.; Lu, P.; et al. Characterization of Serum Small Extracellular Vesicles and Their Small RNA Contents across Humans, Rats, and Mice. Sci. Rep. 2020, 10, 4197. [Google Scholar] [CrossRef]
  41. Salinas-Giegé, T.; Giegé, R.; Giegé, P. TRNA Biology in Mitochondria. Int. J. Mol. Sci. 2015, 16, 4518–4559. [Google Scholar] [CrossRef] [Green Version]
  42. Telonis, A.G.; Kirino, Y.; Rigoutsos, I. Mitochondrial TRNA-Lookalikes in Nuclear Chromosomes: Could They Be Functional? RNA Biol. 2015, 12, 375–380. [Google Scholar] [CrossRef] [Green Version]
  43. Meseguer, S. MicroRNAs and TRNA-Derived Small Fragments: Key Messengers in Nuclear–Mitochondrial Communication. Front. Mol. Biosci. 2021, 8, 203. [Google Scholar] [CrossRef]
  44. Maniataki, E.; Mourelatos, Z. Human Mitochondrial TRNAMet Is Exported to the Cytoplasm and Associates with the Argonaute 2 Protein. RNA 2005, 11, 849–852. [Google Scholar] [CrossRef] [Green Version]
  45. Rubio, M.A.T.; Rinehart, J.J.; Krett, B.; Duvezin-Caubet, S.; Reichert, A.S.; Söll, D.; Alfonzo, J.D. Mammalian Mitochondria Have the Innate Ability to Import TRNAs by a Mechanism Distinct from Protein Import. Proc. Natl. Acad. Sci. USA 2008, 105, 9186–9191. [Google Scholar] [CrossRef] [Green Version]
  46. Fett, J.W.; Strydom, D.J.; Lobb, R.R.; Alderman, E.M.; Bethune, J.L.; Riordan, J.F.; Vallee, B.L. Isolation and Characterization of Angiogenin, an Angiogenic Protein from Human Carcinoma Cells. Biochemistry 1985, 24, 5480–5486. [Google Scholar] [CrossRef]
  47. Li, S.; Ibaragi, S.; Hu, G.-F. Angiogenin as a Molecular Target for the Treatment of Prostate Cancer. Curr. Cancer Ther. Rev. 2012, 7, 83–90. [Google Scholar] [CrossRef] [Green Version]
  48. Saxena, S.K.; Rybak, S.M.; Davey, R.T.; Youle, R.J.; Ackerman, E.J. Angiogenin Is a Cytotoxic, TRNA-Specific Ribonuclease in the RNase A Superfamily. J. Biol. Chem. 1992, 267, 21982–21986. [Google Scholar] [CrossRef]
  49. Cho, S.; Beintema, J.J.; Zhang, J. The Ribonuclease A Superfamily of Mammals and Birds: Identifying New Members and Tracing Evolutionary Histories. Genomics 2005, 85, 208–220. [Google Scholar] [CrossRef]
  50. Nitto, T.; Dyer, K.D.; Czapiga, M.; Rosenberg, H.F. Evolution and Function of Leukocyte RNase A Ribonucleases of the Avian Species, Gallus Gallus. J. Biol. Chem. 2006, 281, 25622–25634. [Google Scholar] [CrossRef] [Green Version]
  51. Sheng, J.; Xu, Z. Three Decades of Research on Angiogenin: A Review and Perspective. Acta Biochim. Biophys. Sin. 2016, 48, 399–410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Pizzo, E.; Buonanno, P.; di Maro, A.; Ponticelli, S.; de Falco, S.; Quarto, N.; Cubellis, M.V.; D’Alessio, G. Ribonucleases and Angiogenins from Fish. J. Biol. Chem. 2006, 281, 27454–27460. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Thompson, D.M.; Parker, R. The RNase Rny1p Cleaves TRNAs and Promotes Cell Death during Oxidative Stress in Saccharomyces Cerevisiae. J. Cell Biol. 2009, 185, 43–50. [Google Scholar] [CrossRef] [PubMed]
  54. Shapiro, R.; Vallee, B.L. Human Placental Ribonuclease Inhibitor Abolishes Both Angiogenic and Ribonucleolytic Activities of Angiogenin. Proc. Natl. Acad. Sci. USA 1987, 84, 2238–2241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Pizzo, E.; Sarcinelli, C.; Sheng, J.; Fusco, S.; Formiggini, F.; Netti, P.; Yu, W.; D’Alessio, G.; Hu, G.F. Ribonuclease/Angiogenin Inhibitor 1 Regulates Stressinduced Subcellular Localization of Angiogenin to Control Growth and Survival. J. Cell Sci. 2013, 126, 4308–4319. [Google Scholar] [CrossRef] [Green Version]
  56. Lai, K.; Luo, C.; Zhang, X.; Ye, P.; Zhang, Y.-D.; He, J.; Yao, K. Regulation of Angiogenin Expression and Epithelial-Mesenchymal Transition by HIF-1α Signaling in Hypoxic Retinal Pigment Epithelial Cells. Biochim. Biophys. Acta-Mol. Basis Dis. 2016, 1862, 1594–1607. [Google Scholar] [CrossRef] [Green Version]
  57. Su, Z.; Kuscu, C.; Malik, A.; Shibata, E.; Dutta, A. Angiogenin Generates Specific Stress-Induced TRNA Halves and Is Not Involved in TRF-3–Mediated Gene Silencing. J. Biol. Chem. 2019, 294, 16930–16941. [Google Scholar] [CrossRef]
  58. Saikia, M.; Krokowski, D.; Guan, B.J.; Ivanov, P.; Parisien, M.; Hu, G.F.; Anderson, P.; Pan, T.; Hatzoglou, M. Genome-Wide Identification and Quantitative Analysis of Cleaved TRNA Fragments Induced by Cellular Stress. J. Biol. Chem. 2012, 287, 42708–42725. [Google Scholar] [CrossRef] [Green Version]
  59. Rybak, S.M.; Vallee, B.L. Base Cleavage Specificity of Angiogenin with Saccharomyces Cerevisiae and Escherichia Coli 5S RNAs. Biochemistry 1988, 27, 2288–2294. [Google Scholar] [CrossRef]
  60. Tosar, J.P.; Gámbaro, F.; Darré, L.; Pantano, S.; Westhof, E.; Cayota, A. Dimerization Confers Increased Stability to Nucleases in 5 Halves from Glycine and Glutamic Acid TRNAs. Nucleic Acids Res. 2018, 46, 9081–9093. [Google Scholar] [CrossRef] [Green Version]
  61. Su, Z.; Wilson, B.; Kumar, P.; Dutta, A. Noncanonical Roles of TRNAs: TRNA Fragments and Beyond. Annu. Rev. Genet. 2020, 54, 47–69. [Google Scholar] [CrossRef] [PubMed]
  62. Megel, C.; Hummel, G.; Lalande, S.; Ubrig, E.; Cognat, V.; Morelle, G.; Salinas-Giegé, T.; Duchêne, A.M.; Maréchal-Drouard, L. Plant RNases T2, but Not Dicer-like Proteins, Are Major Players of TRNA-Derived Fragments Biogenesis. Nucleic Acids Res. 2019, 47, 941–952. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Andersen, K.L.; Collins, K. Several RNase T2 Enzymes Function in Induced TRNA and RRNA Turnover in the Ciliate Tetrahymena. Mol. Biol. Cell 2012, 23, 36–44. [Google Scholar] [CrossRef] [PubMed]
  64. Akiyama, Y.; Lyons, S.; Fay, M.M.; Abe, T.; Anderson, P.; Ivanov, P. Multiple Ribonuclease A Family Members Cleave Transfer RNAs in Response to Stress. bioRxiv 2019, 811174. [Google Scholar] [CrossRef]
  65. Donovan, J.; Rath, S.; Kolet-Mandrikov, D.; Korennykh, A. Rapid RNase L-Driven Arrest of Protein Synthesis in the DsRNA Response without Degradation of Translation Machinery. RNA 2017, 23, 1660–1671. [Google Scholar] [CrossRef] [Green Version]
  66. Nechooshtan, G.; Yunusov, D.; Chang, K.; Gingeras, T.R. Processing by RNase 1 Forms TRNA Halves and Distinct y RNA Fragments in the Extracellular Environment. Nucleic Acids Res. 2020, 48, 8035–8049. [Google Scholar] [CrossRef]
  67. Yang, J.Y.; Deng, X.Y.; Li, Y.S.; Ma, X.C.; Feng, J.X.; Yu, B.; Chen, Y.; Luo, Y.L.; Wang, X.; Chen, M.L.; et al. Structure of Schlafen13 Reveals a New Class of TRNA/RRNA- Targeting RNase Engaged in Translational Control. Nat. Commun. 2018, 9, 1165. [Google Scholar] [CrossRef] [Green Version]
  68. di Fazio, A.; Schlackow, M.; Pong, S.K.; Alagia, A.; Gullerova, M. Dicer Dependent TRNA Derived Small RNAs Promote Nascent RNA Silencing. Nucleic Acids Res. 2022, 50, 1734–1752. [Google Scholar] [CrossRef]
  69. Krishna, S.; Yim, D.G.; Lakshmanan, V.; Tirumalai, V.; Koh, J.L.; Park, J.E.; Cheong, J.K.; Low, J.L.; Lim, M.J.; Sze, S.K.; et al. Dynamic Expression of TRNA-derived Small RNAs Define Cellular States. EMBO Rep. 2019, 20, e47789. [Google Scholar] [CrossRef]
  70. Stefani, G.; Slack, F.J. Small Non-Coding RNAs in Animal Development. Nat. Rev. Mol. Cell Biol. 2008, 9, 219–230. [Google Scholar]
  71. Torres, A.G.; Reina, O.; Attolini, C.S.O.; de Pouplana, L.R. Differential Expression of Human TRNA Genes Drives the Abundance of TRNA-Derived Fragments. Proc. Natl. Acad. Sci. USA 2019, 116, 8451–8456. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Aoi, T.; Yae, K.; Nakagawa, M.; Ichisaka, T.; Okita, K.; Takahashi, K.; Chiba, T.; Yamanaka, S. Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach Cells. Science 2008, 321, 699–702. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Zhang, D.Y.; Ming, G.L.; Song, H. PUS7: A Targetable Epitranscriptomic Regulator of Glioblastoma Growth. Trends Pharmacol. Sci. 2021, 42, 976–978. [Google Scholar] [CrossRef] [PubMed]
  74. Guzzi, N.; Cieśla, M.; Ngoc, P.C.T.; Lang, S.; Arora, S.; Dimitriou, M.; Pimková, K.; Sommarin, M.N.E.; Munita, R.; Lubas, M.; et al. Pseudouridylation of TRNA-Derived Fragments Steers Translational Control in Stem Cells. Cell 2018, 173, 1204–1216.e26. [Google Scholar] [CrossRef] [Green Version]
  75. Lyons, S.M.; Gudanis, D.; Coyne, S.M.; Gdaniec, Z.; Ivanov, P. Identification of Functional Tetramolecular RNA G-Quadruplexes Derived from Transfer RNAs. Nat. Commun. 2017, 8, 1127. [Google Scholar] [CrossRef] [Green Version]
  76. Lyons, S.M.; Kharel, P.; Akiyama, Y.; Ojha, S.; Dave, D.; Tsvetkov, V.; Merrick, W.; Ivanov, P.; Anderson, P. EIF4G Has Intrinsic G-Quadruplex Binding Activity That Is Required for TiRNA Function. Nucleic Acids Res 2020, 48, 6223–6233. [Google Scholar] [CrossRef]
  77. Yuan, Y.; Li, J.; He, Z.; Fan, X.; Mao, X.; Yang, M.; Yang, D. Trna-Derived Fragments as New Hallmarks of Aging and Age-Related Diseases. Aging Dis. 2021, 12, 1304–1322. [Google Scholar] [CrossRef]
  78. Victoria, B.; Dhahbi, J.M.; Nunez Lopez, Y.O.; Spinel, L.; Atamna, H.; Spindler, S.R.; Masternak, M.M. Circulating MicroRNA Signature of Genotype-by-Age Interactions in the Long-Lived Ames Dwarf Mouse. Aging Cell 2015, 14, 1055–1066. [Google Scholar] [CrossRef]
  79. Zhu, L.; Li, T.; Shen, Y.; Yu, X.; Xiao, B.; Guo, J. Using TRNA Halves as Novel Biomarkers for the Diagnosis of Gastric Cancer. Cancer Biomark. 2019, 25, 169–176. [Google Scholar] [CrossRef]
  80. Ivanov, P.; Emara, M.M.; Villen, J.; Gygi, S.P.; Anderson, P. Angiogenin-Induced TRNA Fragments Inhibit Translation Initiation. Mol. Cell 2011, 43, 613–623. [Google Scholar] [CrossRef] [Green Version]
  81. Mo, D.; Jiang, P.; Yang, Y.; Mao, X.; Tan, X.; Tang, X.; Wei, D.; Li, B.; Wang, X.; Tang, L.; et al. A TRNA Fragment, 5’-TiRNAVal, Suppresses the Wnt/β-Catenin Signaling Pathway by Targeting FZD3 in Breast Cancer. Cancer Lett. 2019, 457, 60–73. [Google Scholar] [CrossRef] [PubMed]
  82. Ormseth, M.J.; Wu, Q.; Zhao, S.; Allen, R.M.; Solus, J.; Sheng, Q.; Guo, Y.; Ye, F.; Ramirez-Solano, M.; Bridges, S.L.; et al. Circulating Microbial Small RNAs Are Altered in Patients with Rheumatoid Arthritis. Ann. Rheum. Dis. 2020, 79, 1557–1564. [Google Scholar] [CrossRef] [PubMed]
  83. Lu, H.; Liu, L.; Han, S.; Wang, B.; Qin, J.; Bu, K.; Zhang, Y.; Li, Z.; Ma, L.; Tian, J.; et al. Expression of TiRNA and TRF in APP/PS1 Transgenic Mice and the Change of Related Proteins Expression. Ann. Transl. Med. 2021, 9, 1457. [Google Scholar] [CrossRef]
  84. Nätt, D.; Kugelberg, U.; Casas, E.; Nedstrand, E.; Zalavary, S.; Henriksson, P.; Nijm, C.; Jäderquist, J.; Sandborg, J.; Flinke, E.; et al. Human Sperm Displays Rapid Responses to Diet. PLoS Biol. 2019, 17, e3000559. [Google Scholar] [CrossRef] [Green Version]
  85. Peng, H.; Shi, J.; Zhang, Y.; Zhang, H.; Liao, S.; Li, W.; Lei, L.; Han, C.; Ning, L.; Cao, Y.; et al. A Novel Class of TRNA-Derived Small RNAs Extremely Enriched in Mature Mouse Sperm. Cell Res. 2012, 22, 1609–1612. [Google Scholar] [CrossRef]
  86. Donkin, I.; Versteyhe, S.; Ingerslev, L.R.; Qian, K.; Mechta, M.; Nordkap, L.; Mortensen, B.; Appel, E.V.R.; Jørgensen, N.; Kristiansen, V.B.; et al. Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans. Cell Metab. 2016, 23, 369–378. [Google Scholar] [CrossRef] [Green Version]
  87. Jeltsch, A.; Ehrenhofer-Murray, A.; Jurkowski, T.P.; Lyko, F.; Reuter, G.; Ankri, S.; Nellen, W.; Schaefer, M.; Helm, M. Mechanism and Biological Role of Dnmt2 in Nucleic Acid Methylation. RNA Biol. 2017, 14, 1108–1123. [Google Scholar] [CrossRef] [Green Version]
  88. Hua, M.; Liu, W.; Chen, Y.; Zhang, F.; Xu, B.; Liu, S.; Chen, G.; Shi, H.; Wu, L. Identification of Small Non-Coding RNAs as Sperm Quality Biomarkers for in Vitro Fertilization. Cell Discov. 2019, 5, 20. [Google Scholar] [CrossRef] [Green Version]
  89. Keam, S.P.; Young, P.E.; McCorkindale, A.L.; Dang, T.H.Y.; Clancy, J.L.; Humphreys, D.T.; Preiss, T.; Hutvagner, G.; Martin, D.I.K.; Cropley, J.E.; et al. The Human Piwi Protein Hiwi2 Associates with TRNA-Derived PiRNAs in Somatic Cells. Nucleic Acids Res. 2014, 42, 8984–8995. [Google Scholar] [CrossRef]
  90. Kazimierczyk, M.; Jędroszkowiak, A.; Kowalczykiewicz, D.; Szymański, M.; Imiołczyk, B.; Ciesiołka, J.; Wrzesiński, J. TRNA-Derived Fragments from the Sus Scrofa Tissues Provide Evidence of Their Conserved Role in Mammalian Development. Biochem. Biophys. Res. Commun. 2019, 520, 514–519. [Google Scholar] [CrossRef]
  91. Tait, S.W.G.; Green, D.R. Mitochondria and Cell Death: Outer Membrane Permeabilization and Beyond. Nat. Rev. Mol. Cell Biol. 2010, 11, 621–632. [Google Scholar]
  92. Saikia, M.; Jobava, R.; Parisien, M.; Putnam, A.; Krokowski, D.; Gao, X.-H.; Guan, B.-J.; Yuan, Y.; Jankowsky, E.; Feng, Z.; et al. Angiogenin-Cleaved TRNA Halves Interact with Cytochrome c, Protecting Cells from Apoptosis during Osmotic Stress. Mol. Cell. Biol. 2014, 34, 2450–2463. [Google Scholar] [CrossRef] [Green Version]
  93. Chen, Y.; Shen, J. Mucosal Immunity and TRNA, TRF, and TiRNA. J. Mol. Med. 2021, 99, 47–56. [Google Scholar] [CrossRef]
  94. Xie, Y.; Yao, L.; Yu, X.; Ruan, Y.; Li, Z.; Guo, J. Action Mechanisms and Research Methods of TRNA-Derived Small RNAs. Signal Transduct. Target. Ther. 2020, 5, 109. [Google Scholar] [CrossRef]
  95. Pandey, K.K.; Madhry, D.; Ravi Kumar, Y.S.; Malvankar, S.; Sapra, L.; Srivastava, R.K.; Bhattacharyya, S.; Verma, B. Regulatory Roles of TRNA-Derived RNA Fragments in Human Pathophysiology. Mol. Ther.-Nucleic Acids 2021, 26, 161–173. [Google Scholar]
  96. Pawar, K.; Shigematsu, M.; Sharbati, S.; Kirino, Y. Infection-Induced 50-Half Molecules of TRNAHisGUG Activate Toll-like Receptor 7. PLoS Biol. 2020, 18, e3000982. [Google Scholar] [CrossRef]
  97. Chiou, N.T.; Kageyama, R.; Ansel, K.M. Selective Export into Extracellular Vesicles and Function of TRNA Fragments during T Cell Activation. Cell Rep. 2018, 25, 3356–3370.e4. [Google Scholar] [CrossRef] [Green Version]
  98. Villarroya-Beltri, C.; Gutiérrez-Vázquez, C.; Sánchez-Cabo, F.; Pérez-Hernández, D.; Vázquez, J.; Martin-Cofreces, N.; Martinez-Herrera, D.J.; Pascual-Montano, A.; Mittelbrunn, M.; Sánchez-Madrid, F. Sumoylated HnRNPA2B1 Controls the Sorting of MiRNAs into Exosomes through Binding to Specific Motifs. Nat. Commun. 2013, 4, 2980. [Google Scholar] [CrossRef] [Green Version]
  99. Shurtleff, M.J.; Temoche-Diaz, M.M.; Karfilis, K.V.; Ri, S.; Schekman, R. Y-Box Protein 1 Is Required to Sort MicroRNAs into Exosomes in Cells and in a Cell-Free Reaction. Elife 2016, 5, e19276. [Google Scholar] [CrossRef]
  100. McNab, F.W.; Ewbank, J.; Rajsbaum, R.; Stavropoulos, E.; Martirosyan, A.; Redford, P.S.; Wu, X.; Graham, C.M.; Saraiva, M.; Tsichlis, P.; et al. TPL-2–ERK1/2 Signaling Promotes Host Resistance against Intracellular Bacterial Infection by Negative Regulation of Type I IFN Production. J. Immunol. 2013, 191, 1732–1743. [Google Scholar] [CrossRef] [Green Version]
  101. vanLoosdregt, J.; Fleskens, V.; Tiemessen, M.M.; Mokry, M.; VanBoxtel, R.; Meerding, J.; Pals, C.E.G.M.; Kurek, D.; Baert, M.R.M.; Delemarre, E.M.; et al. Canonical Wnt Signaling Negatively Modulates Regulatory T Cell Function. Immunity 2013, 39, 298–310. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Dhahbi, J.M. 5′ TRNA Halves: The next Generation of Immune Signaling Molecules. Front. Immunol. 2015, 6, 74. [Google Scholar] [CrossRef] [Green Version]
  103. Samir, M.; Pessler, F. Small Non-Coding RNAs Associated with Viral Infectious Diseases of Veterinary Importance: Potential Clinical Applications. Front. Vet. Sci. 2016, 3, 22. [Google Scholar] [CrossRef]
  104. Wang, Y.; Zhang, Y.; Kong, L.; Song, C.; Chen, X.; Fang, X.; Zhang, C. TRNA-Derived RNA Fragments in the Exosomes of Bovine Milk and Colostrum. J. Food Compos. Anal. 2021, 102, 103948. [Google Scholar] [CrossRef]
  105. Liu, Q.Y.; Gu, X.R.; Zhao, Y.Q.; Zhang, J.; Zhao, Y.F.; Meng, Q.Y.; Xu, G.H.; Hu, X.X.; Li, N. Pig Large Tumor Suppressor 2 (Lats2), a Novel Gene That May Regulate the Fat Reduction in Adipocyte. BMB Rep. 2010, 43, 97–102. [Google Scholar] [CrossRef] [Green Version]
  106. Tao, E.-W.; Wang, H.-L.; Cheng, W.Y.; Liu, Q.-Q.; Chen, Y.-X.; Gao, Q.-Y. A Specific TRNA Half, 5′tiRNA-His-GTG, Responds to Hypoxia via the HIF1α/ANG Axis and Promotes Colorectal Cancer Progression by Regulating LATS2. J. Exp. Clin. Cancer Res. 2021, 40, 67. [Google Scholar] [CrossRef]
  107. Bordoni, L.; Gabbianelli, R. The Neglected Nutrigenomics of Milk: What Is the Role of Inter-Species Transfer of Small Non-Coding RNA? Food Biosci. 2021, 39, 100796. [Google Scholar] [CrossRef]
  108. Taxis, T.M.; Bauermann, F.V.; Ridpath, J.F.; Casas, E. Analysis of TRNA Halves (TsRNAs) in Serum from Cattle Challenged with Bovine Viral Diarrhea Virus. Genet. Mol. Biol. 2019, 42, 374–379. [Google Scholar] [CrossRef]
  109. Ivanov, P. Emerging Roles of TRNA-Derived Fragments in Viral Infections: The Case of Respiratory Syncytial Virus. Mol. Ther. 2015, 23, 1557–1558. [Google Scholar] [CrossRef]
  110. Taxis, T.M.; Kehrli, M.E.; D’Orey-Branco, R.; Casas, E. Association of Transfer RNA Fragments in White Blood Cells with Antibody Response to Bovine Leukemia Virus in Holstein Cattle. Front. Genet. 2018, 9, 236. [Google Scholar] [CrossRef]
  111. Casas, E.; Cai, G.; Kuehn, L.A.; Register, K.B.; McDaneld, T.G.; Neill, J.D. Association of Circulating Transfer RNA Fragments with Antibody Response to Mycoplasma Bovis in Beef Cattle. BMC Vet. Res. 2018, 14, 89. [Google Scholar] [CrossRef]
  112. Fricker, R.; Brogli, R.; Luidalepp, H.; Wyss, L.; Fasnacht, M.; Joss, O.; Zywicki, M.; Helm, M.; Schneider, A.; Cristodero, M.; et al. A TRNA Half Modulates Translation as Stress Response in Trypanosoma Brucei. Nat. Commun. 2019, 10, 118. [Google Scholar] [CrossRef] [Green Version]
  113. Hotamisligil, G.S.; Davis, R.J. Cell Signaling and Stress Responses. Cold Spring Harb. Perspect. Biol. 2016, 8, a006072. [Google Scholar] [CrossRef] [Green Version]
  114. Campos-Melo, D.; Hawley, Z.C.E.; Droppelmann, C.A.; Strong, M.J. The Integral Role of RNA in Stress Granule Formation and Function. Front. Cell Dev. Biol. 2021, 9, 808. [Google Scholar] [CrossRef]
  115. Haack, F.; Trakooljul, N.; Gley, K.; Murani, E.; Hadlich, F.; Wimmers, K.; Ponsuksili, S. Deep Sequencing of Small Non-Coding RNA Highlights Brain-Specific Expression Patterns and RNA Cleavage. RNA Biol. 2019, 16, 1764–1774. [Google Scholar] [CrossRef]
  116. Gley, K.; Hadlich, F.; Trakooljul, N.; Haack, F.; Murani, E.; Gimsa, U.; Wimmers, K.; Ponsuksili, S. Multi-Transcript Level Profiling Revealed Distinct MRNA, MiRNA, and TRNA-Derived Fragment Bio-Signatures for Coping Behavior Linked Haplotypes in HPA Axis and Limbic System. Front. Genet. 2021, 12, 1558. [Google Scholar] [CrossRef]
  117. Jehn, J.; Treml, J.; Wulsch, S.; Ottum, B.; Erb, V.; Hewel, C.; Kooijmans, R.N.; Wester, L.; Fast, I.; Rosenkranz, D. 5′ TRNA Halves Are Highly Expressed in the Primate Hippocampus and Might Sequence-Specifically Regulate Gene Expression. RNA 2020, 26, 694–707. [Google Scholar] [CrossRef] [Green Version]
  118. Kumar, P.; Kuscu, C.; Dutta, A. Biogenesis and Function of Transfer RNA-Related Fragments (TRFs). Trends Biochem. Sci. 2016, 41, 679–689. [Google Scholar] [CrossRef] [Green Version]
  119. Kumar, P.; Mudunuri, S.B.; Anaya, J.; Dutta, A. TRFdb: A Database for Transfer RNA Fragments. Nucleic Acids Res. 2015, 43, D141–D145. [Google Scholar] [CrossRef]
  120. la Ferlita, A.; Alaimo, S.; Veneziano, D.; Nigita, G.; Balatti, V.; Croce, C.M.; Ferro, A.; Pulvirenti, A. Identification of TRNA-Derived NcRNAs in TCGA and NCI-60 Panel Cell Lines and Development of the Public Database TRFexplorer. Database 2019, 2019, 115. [Google Scholar] [CrossRef]
  121. Zuo, Y.; Zhu, L.; Guo, Z.; Liu, W.; Zhang, J.; Zeng, Z.; Wu, Q.; Cheng, J.; Fu, X.; Jin, Y.; et al. TsRBase: A Comprehensive Database for Expression and Function of TsRNAs in Multiple Species. Nucleic Acids Res. 2021, 49, D1038–D1045. [Google Scholar] [CrossRef]
  122. Chan, P.P.; Lowe, T.M. GtRNAdb 2.0: An Expanded Database of Transfer RNA Genes Identified in Complete and Draft Genomes. Nucleic Acids Res. 2016, 44, D184–D189. [Google Scholar] [CrossRef] [Green Version]
  123. Dhahbi, J.M. Circulating Small Noncoding RNAs as Biomarkers of Aging. Ageing Res. Rev. 2014, 17, 86–98. [Google Scholar] [CrossRef]
  124. Miretti, S.; Lecchi, C.; Ceciliani, F.; Baratta, M. MicroRNAs as Biomarkers for Animal Health and Welfare in Livestock. Front. Vet. Sci. 2020, 7, 985. [Google Scholar] [CrossRef]
  125. Fleming, D.S.; Miller, L.C. Differentially Expressed MiRNAs and TRNA Genes Affect Host Homeostasis during Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Infections in Young Pigs. Front. Genet. 2019, 10, 691. [Google Scholar] [CrossRef] [Green Version]
Ncrna 08 00037 g001 550
Figure 1. Classification of tRNA-derived fragments (tsRNAs) into tRF and tiRNA (tRNA halves). Graphical representation describing the exonuclease activity of angiogenin and Dicer to digest mature tRNAs.
Figure 1. Classification of tRNA-derived fragments (tsRNAs) into tRF and tiRNA (tRNA halves). Graphical representation describing the exonuclease activity of angiogenin and Dicer to digest mature tRNAs.
Ncrna 08 00037 g001
Ncrna 08 00037 g002 550
Figure 2. (a) Known RNases involved in tsRNA biosynthesis. (b) Known enzymes involved in tRNA modification.
Figure 2. (a) Known RNases involved in tsRNA biosynthesis. (b) Known enzymes involved in tRNA modification.
Ncrna 08 00037 g002
Ncrna 08 00037 g003 550
Figure 3. Cleavage of specific tRNAs in 5′-tiRNAs can bind the G4 complex, displacing the elF4F factor and consecutively suppressing the translation by creating an RNA G-quadruplex (RG4s) on the mRNA cap that inhibits translation initiation complex.
Figure 3. Cleavage of specific tRNAs in 5′-tiRNAs can bind the G4 complex, displacing the elF4F factor and consecutively suppressing the translation by creating an RNA G-quadruplex (RG4s) on the mRNA cap that inhibits translation initiation complex.
Ncrna 08 00037 g003
Ncrna 08 00037 g004 550
Figure 4. The stimulation of the membrane by TLR activates NF-kB and leads to overexpression of ANG. Angiogenin cleaves the anticodon loops of tRNAs producing 5′-tiRNAs that are secreted as signalling molecules after being packed into EVs. TLR-7 is activated when the complex EV-5′-tiRNAs are transported into endosomes in targeted cells, followed by the activation of immunological responses.
Figure 4. The stimulation of the membrane by TLR activates NF-kB and leads to overexpression of ANG. Angiogenin cleaves the anticodon loops of tRNAs producing 5′-tiRNAs that are secreted as signalling molecules after being packed into EVs. TLR-7 is activated when the complex EV-5′-tiRNAs are transported into endosomes in targeted cells, followed by the activation of immunological responses.
Ncrna 08 00037 g004
Ncrna 08 00037 g005 550
Figure 5. 5′-tiRNAVal downregulates the Wnt/β-catenin signalling pathway by targeting FZD3 gene expression.
Figure 5. 5′-tiRNAVal downregulates the Wnt/β-catenin signalling pathway by targeting FZD3 gene expression.
Ncrna 08 00037 g005
Ncrna 08 00037 g006 550
Figure 6. Stress granule formation is mediated by tiRNAs. 5’-tiRNAs promote the formation of stress granules (SGs), phase-separated cytoplasmic ribonucleoproteins assemblies lacking in membranes that condense mRNAs, ribosomal components, RNA binding proteins, and translation initiation factors [114], in response to stress conditions such as hypoxia and heat shock. Through the activation of NF-κB and PKR, SGs play a role in immunity. SGs reduce the production of NFKBIA mRNA, which would normally block the NF-κB pathway during the inflammatory process. As a result, SGs boost the NF-κB pathway. Virus infection also increases the association of G3BP1, Caprin1, and PKR, resulting in the G3BP1-Caprin1-PKR complex. SGs play a role in PKR activation through the G3BP1-Caprin1-PKR complex.
Figure 6. Stress granule formation is mediated by tiRNAs. 5’-tiRNAs promote the formation of stress granules (SGs), phase-separated cytoplasmic ribonucleoproteins assemblies lacking in membranes that condense mRNAs, ribosomal components, RNA binding proteins, and translation initiation factors [114], in response to stress conditions such as hypoxia and heat shock. Through the activation of NF-κB and PKR, SGs play a role in immunity. SGs reduce the production of NFKBIA mRNA, which would normally block the NF-κB pathway during the inflammatory process. As a result, SGs boost the NF-κB pathway. Virus infection also increases the association of G3BP1, Caprin1, and PKR, resulting in the G3BP1-Caprin1-PKR complex. SGs play a role in PKR activation through the G3BP1-Caprin1-PKR complex.
Ncrna 08 00037 g006
Ncrna 08 00037 g007 550
Figure 7. Reported tsRNAs in Homo sapiens, Sus scrofa, Gallus gallus, and Bos taurus on tsRBase.
Figure 7. Reported tsRNAs in Homo sapiens, Sus scrofa, Gallus gallus, and Bos taurus on tsRBase.
Ncrna 08 00037 g007
Table
Table 1. Mammalian non-coding RNA classes.
Table 1. Mammalian non-coding RNA classes.
ClassSymbolCharacteristicsBiological Functions
Associations		Ref.
Small non-coding RNAs (sncRNAs)MicroRNAsmiRNAs18–26 nt; comprises 2% of human genome and regulate up to 50% of protein-coding genes.Control of proliferation, apoptosis, and differentiation.[9]
Small interfering RNAssiRNA19–23 nt; processed by Dicer, and guide sequence-specific degradation of target mRNA.Post-transcriptional regulation of gene expression.[10]
Piwi-interacting RNAspiRNAs24–31 nt; made by single-stranded RNA (ssRNA) precursors and it is Dicer-independent.Embryonic development, germline DNA integrity, transposon transcription silencing, translation suppression, heterochromatin creation, and sex determination epigenetic control.[11]
Small nucleolar RNAssnoRNAs60–300 nt; divided into two classes: C/D box snoRNAs and H/ACA box snoRNAs. It is primarily accumulated in the nucleoli.Responsible for post-transcriptional modification and maturation of ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and other RNAs (snRNAs).[12]
Centromere repeat-associated small interacting RNAscrasiRNAs34–42 nt; processed from long dsRNAs.Activation of heterochromatin and centromeric proteins.[13]
Telomere-specific small RNAstel-sRNAs~24 nt; pi-like small RNA and independent of Dicer processing.Epigenetic regulation.[14]
Pyknons >16 nt long; observed in groups in intergenic and intronic domains.Primarily engaged in cell communication, transcriptional regulation, signalling, and transport.[15]
tRNA fragmentstRFs14–30 nt; dependent on angiogenin and Dicer processing.Diverse molecular and physiological processes, including gene suppression, RNA processing, protein translation, stress responses, cell proliferation, and differentiation.[16]
tRNA-derived stress-induced RNAstiRNAs (tRNA halves)29–50 nt; the most abundant right downstream of transcriptional end sites. It exhibits spatial preservation patterns and predominantly resides in GC-rich promoters.Control of protein-coding gene transcription by targeting epigenetic silencing complexes.[17]
Table
Table 2. ANG and pseudogenes discovered in mammals and higher vertebrates.
Table 2. ANG and pseudogenes discovered in mammals and higher vertebrates.
SpeciesANGProtein LengthRef.
Human (H. sapiens)1147 aa[49]
Mouse (M. musculus)5 (3 pseudogenes)145 aa[49]
Rat (R. norvegicus)2145 aa[49]
Dog (C. lupus familiaris)1145 aa[50]
Cattle (B. Taurus)3148 aa[50]
Pig (S. scrofa)2202 aa[51]
Rabbit (O. cuniculus)1149 aa[51]
Rainbow trout (O. mykiss)6205 aa[52]
Zebrafish (D. rerio)5149 aa[52]
Table
Table 3. tiRNAs linked to aging hallmarks and aging-related diseases.
Table 3. tiRNAs linked to aging hallmarks and aging-related diseases.
Aging
Hallmarks 		tiRNA IDtiRNA TypeGene or
Protein Target		MechanismRef.
Cellular senescencetiRNA-5034-GluTTC-25′-tiRNA-Downregulated in cancer tissue, and the degree of expression is inversely related to tumour growth.[79]
tiRNALys5′-tiRNA-Regulation of aging hallmarks[78]
Loss of proteostasistiRNAAla5′-tiRNAelF2aInhibits protein synthesis[80]
tiRNACys5′-tiRNAelF2aInhibits protein synthesis[80]
tiRNAVal5′-tiRNAFZD3Regulation of WNT/β-Catenin pathway[81]
Aging related diseasestiRNAAsnGTT
tiRNAIleAAT
tiRNAAspGTC		5′-tiRNA-Downregulation observed in rheumatoid arthritis patients[82]
tRNAVal
derived		5′-tiRNA
3′-tiRNA		Aβ/TauMay inhibit Aβ production and Tau protein hyperphosphorylation in Alzheimer’s disease [83]
Table
Table 4. tiRNAs involved in some human and farm animal infectious diseases.
Table 4. tiRNAs involved in some human and farm animal infectious diseases.
DiseasetiRNA IDtiRNA TypeMechanismRef.
Bovine viral diarrhoea virus (BVDV)tiRNaGlyCCC
tiRNAGlyGCC		5′-tiRNAIt is downregulated, it may define the immune response against BVDV[108]
Respiratory syncytial virus (RSV)tiRNAGluCTC
tiRNAGlu		5′-tiRNARSV promotes ANG expression, and then cleaves specific tRNAs that may inhibit APOER2 production[109]
Bovine Leukemia
Virus (BLV)		tiRNAGlnCTG
tiRNAGlnTTG
tiRNAHisGTG		5′-tiRNAIt targets white blood cells causing dysregulated immune functions and immunosuppression.[110]
Mycoplasma bovistiRNASelCysUGA5′-tiRNAIt may be correlated with a host defence mechanism enhanced by bacterial infection.[111]
Trypanosoma brucei (rHAT)tiRNAThr3′-tiRNADuring the stress recovery phase, it attaches to the ribosome and increases protein production.[112]
Table
Table 5. tRNA Gene Summary of Homo sapiens, Sus scrofa, Gallus gallus, and Bos taurus on GtRNAdb v2 (accessed on 9 April 2022).
Table 5. tRNA Gene Summary of Homo sapiens, Sus scrofa, Gallus gallus, and Bos taurus on GtRNAdb v2 (accessed on 9 April 2022).
OrganismtRNA Decoding
Standard 20AA		TCA Suppressor
tRNAs		Genome Version
H. sapiens4151Feb.2009 GRCh37/hg19
S. scrofa4711Feb.2017 Sscrofa11.1
G. gallus2801Mar.2018 GRCg6a
B. taurus6191Apr.2018 ARS-UCD1.2/bosTau9
Table
Table 6. tiRNAs and tFRs databases including mammals and other vertebrates.
Table 6. tiRNAs and tFRs databases including mammals and other vertebrates.
NameDescriptionLink (accessed on 9 April 2022)
tRFexplorerPublicly accessible database that allows users to view the expression profiles of tRNA-derived ncRNAs in each NCI-60 cell line.https://trfexplorer.cloud/
tRFdbThe first database of transfer RNA fragments (tRFs)http://genome.bioch.virginia.edu/trfdb/
tsRBaseMulti-species database of tsRNA sequences, expression characteristics, and function.http://www.tsrbase.org/
GtRNAdb v2tRNA gene predictions on complete or nearly complete genomes.http://gtrnadb.ucsc.edu/GtRNAdb2/
tDRnamerStandardised naming for tRNA-derived RNAshttp://trna.ucsc.edu/tDRnamer/
tRAXIn-depth analysis of tRNA-derived small RNAs (tDRs), mature tRNAs, and RNA modification inference from high-throughput small RNA sequencing data.http://trna.ucsc.edu/tRAX
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Sarais, F.; Perdomo-Sabogal, A.; Wimmers, K.; Ponsuksili, S. tiRNAs: Insights into Their Biogenesis, Functions, and Future Applications in Livestock Research. Non-Coding RNA 2022, 8, 37. https://doi.org/10.3390/ncrna8030037

AMA Style

Sarais F, Perdomo-Sabogal A, Wimmers K, Ponsuksili S. tiRNAs: Insights into Their Biogenesis, Functions, and Future Applications in Livestock Research. Non-Coding RNA. 2022; 8(3):37. https://doi.org/10.3390/ncrna8030037

Chicago/Turabian Style

Sarais, Fabio, Alvaro Perdomo-Sabogal, Klaus Wimmers, and Siriluck Ponsuksili. 2022. "tiRNAs: Insights into Their Biogenesis, Functions, and Future Applications in Livestock Research" Non-Coding RNA 8, no. 3: 37. https://doi.org/10.3390/ncrna8030037

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop