Dynamics of tRNA fragments and their targets in aging mammalian brain

Abstract

Background: The progress of next-generation sequencing technologies has unveiled various non-coding RNAs that have previously been considered products of random degradation and attracted only minimal interest. Among small RNA families, microRNA (miRNAs) have traditionally been considered key post-transcriptional regulators. However, recent studies have reported evidence for widespread presence of fragments of tRNA molecules (tRFs) across a range of organisms and tissues, and of tRF involvement in Argonaute complexes. Methods:To elucidate potential tRF functionality, we compared available RNA sequencing datasets derived from the brains of young, mid-aged and old rats. Using sliding 7-mer windows along a tRF, we searched for putative seed sequences with high numbers of conserved complementary sites within 3' UTRs of 23 vertebrate genomes. We analyzed Gene Ontology term enrichment of predicted tRF targets and compared their transcript levels with targets of miRNAs in the context of age. Results and Discussion: We detected tRFs originating from 3’- and 5’-ends of tRNAs in rat brains at significant levels. These fragments showed dynamic changes: 3’ tRFs monotonously increased with age, while 5’ tRFs displayed less consistent patterns. Furthermore, 3’ tRFs showed a narrow size range compared to 5’ tRFs, suggesting a difference in their biogenesis mechanisms. Similar to our earlier results in Drosophila and compatible with other experimental findings, we found “seed” sequence locations on both ends of different tRFs. Putative targets of these fragments were found to be enriched in neuronal and developmental functions. Comparison of tRFs and miRNAs increasing in abundance with age revealed small, but distinct changes in brain target transcript levels for these two types of small RNA, with the higher proportion of tRF targets decreasing with age. We also illustrated the utility of tRF analysis for annotating tRNA genes in sequenced genomes.

tRNA fragments (tRFs) populations analysis in mutants affecting tRNAs processing and tRNA methylation

“…Despite several reports published during the last years describing tRFs in different organisms, a standardized procedure to exhaustively analyze this small RNA populations, in particular using already available small RNA libraries is still lacking. Indeed, each study uses workflows with different parameters, including small RNA preparation, the number of permitted mismatches (0-3 mismatches), the length of analyzed reads, or the way the genome reference has been built (Wang et al, 2013;Goodarzi et al, 2015;Karaiskos et al, 2015aKaraiskos et al, , 2015bKumar et al, 2015;Grigoriev and Karaiskos, 2016;Göktaş et al, 2017;Schorn et al, 2017;Shen et al, 2018;Siira et al, 2018;Kuscu et al, 2018;Liu et al, 2018;Su et al, 2019;Guan et al, 2019). Some studies have modified the genome reference to have pre-tRNAs sequences, but the number of downstream sequences can vary; some have removed introns from the genome reference; some studies have added CCA tag to the genomic reference to recover 3'CCA-tRFs but others have allowed 3 mismatches, then trimmed the CCA tag from reads to match them against the mature tRNA genome reference.…”

“…Describing mitochondrial tRFs biogenesis thus help to better understand the molecular mechanisms linked to these pathologies. Interestingly, tRFs have been shown to be present in the brain of different species, and tRFs population can vary with age in Drosophila (Karaiskos et al, 2015a(Karaiskos et al, , 2015bGrigoriev and Karaiskos, 2016;Angelova et al, 2018).…”

Genome-wide identification of functional tRNA-derived fragments in Senescence-accelerated mouse prone 8 brain

“…Given their widespread presence, the tRFs are expected to play key roles in many physiological and pathological processes. With aging, tRFs undergo dynamic changes in the mammalian brain (Karaiskos and Grigoriev 2016). Getting older underlies cognitive decline and dementia, and is the most dangerous element for the failure of brain function.…”

“…Many studies have shown that tRFs have specific biological roles and are implicated in mediating complex pathological processes of diverse illnesses, such as cancer and viral infectious disease (Zhou et al 2017;Yeung et al 2009;Guzman et al 2015). A well-studied research revealed that tRFs are associated with mammalian brain aging (Karaiskos and Grigoriev 2016). tRFs have the potential effect in neurodegenerative processes (Hanada et al 2013;Ivanov et al 2014).…”

RNA-sequencing reveals the expression profiles of tsRNAs and their potential carcinogenic role in cholangiocarcinoma

“…Similar to miRNAs, tsRNAs also can bind to Argonaute proteins (15,16). It's reported that tRFs, similar to miRNAs, can target mRNA (16)(17)(18). Furthermore, some studies suggested that the seed sequences of tRFs have spectra analogous to those of miRNAs (16,19,20).…”