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Dynamics of tRNA Fragments and Their Targets in Aging Mammalian Brain

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Dynamics of tRNA Fragments and Their Targets in Aging Mammalian Brain

Spyros Karaiskos et al. F1000Res.

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.

Keywords: aging; non-coding RNA; rat brain; rat cortex; tRNA fragments; transfer RNA.

Conflict of interest statement

No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Typical endpoints of tRNA fragments.
Typical secondary structure representation for the PheGAA tRNA gene (from http://trnadb.bioinf.uni-leipzig.de). Blue arrows point to typical endpoints for a 5' tRF. Red arrows indicate the ends of the most frequent 3' tRF. The mature tRNA molecule also contains the post-transcriptional 3' CCA modification (as does the 3' tRF). A 3' U tRF would derive from the uracil-rich trailer sequence downstream of the end of the tRNA gene (not shown).
Figure 2.
Figure 2.. Differences in length distribution of tRFs.
Length distributions for 5' (blue) and 3' (red) tRFs. tRF length is shown on the x-axis and the frequency on the y-axis. Note the much broader variability for the 5’ tRFs.
Figure 3.
Figure 3.. Age-related change in 3' tRF levels.
Abundance of 3' tRFs in rat brains for 3 distinct time points (Y is shown in green, M in blue and O in red). An average of 3 replicates for each tRF is shown on the x-axis for each time point. Error bars indicate the range of read counts. The y-axis shows the normalized tRF abundance; the numbers on the x-axis correspond to tRNA genes listed in Table 2. Y, young (6 months); M, mid-age (14 months); O, old (22 months).
Figure 4.
Figure 4.. Age-related change in 5' tRF levels.
Abundance of 5' tRFs in rat brains for 3 distinct time points (Y is shown in green, M in blue and O in red). An average of 3 replicates for each tRF is shown on the x-axis for each time point. Error bars indicate the range of read counts. The y-axis shows the normalized tRF abundance; the numbers on the x axis correspond to tRNA genes listed in Table 2. Y, young (6 months); M, mid-age (14 months); O, old (22 months).
Figure 5.
Figure 5.. Total tRF abundance.
Change in total abundance levels with age for all 5' tRFs (blue) and 3' tRFs (red). Y, young (6 months); M, mid-age (14 months); O, old (22 months).
Figure 6.
Figure 6.. Candidate seed region locations for tRFs.
The numbers of exact sequence matches in the 3’ UTR regions are plotted against the starting position of a 7-mer. Expected number of matches in 3' UTRs is shown in yellow, average number of conserved matches for all other 7-mers with the same nucleotide composition as the given window is shown in blue, and the observed number of matches in the conserved regions of 23 vertebrates is shown in red. The letters on the top left corners of each plot correspond to individual tRFs: ( A) ProTGG, ( B) ValAAC, ( C) PheGAA, ( D) AlaTGC, ( E) SerAGA and ( F) SerGCT.
Figure 7.
Figure 7.. Changes in target transcript levels with age.
Transcript level changes from young to old rat brains. Distributions of changes for all detectable mRNAs in rat brains (blue), miRNA-targeted (green) and 3' tRF-targeted transcripts (red) are shown using 2.5% bins.

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Grant support

This work was in part supported by the National Science Foundation to AG [DBI-1458202].

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