Abstract
BackgroundtRFs, 14 to 32 nt long single-stranded RNA derived from mature or precursor tRNAs, are a recently discovered class of small RNA that have been found to be present in diverse organisms at read counts comparable to miRNAs. Currently, there is a debate about their biogenesis and function.ResultsThis is the first meta-analysis of tRFs. Analysis of more than 50 short RNA libraries has revealed that tRFs are precisely generated fragments present in all domains of life (bacteria to humans), and are not produced by the miRNA biogenesis pathway. Human PAR-CLIP data shows a striking preference for tRF-5s and tRF-3s to associate with AGO1, 3 and 4 rather than AGO2, and analysis of positional T to C mutational frequency indicates these tRFs associate with Argonautes in a manner similar to miRNAs. The reverse complements of canonical seed positions in these sequences match cross-link centered regions, suggesting these tRF-5s and tRF-3s interact with RNAs in the cell. Consistent with these results, human AGO1 CLASH data contains thousands of tRF-5 and tRF-3 reads chimeric with mRNAs.ConclusionstRFs are an abundant class of small RNA present in all domains of life whose biogenesis is distinct from miRNAs. In human HEK293 cells tRFs associate with Argonautes 1, 3 and 4 and not Argonaute 2 which is the main effector protein of miRNA function, but otherwise have very similar properties to miRNAs, indicating tRFs may play a major role in RNA silencing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-014-0078-0) contains supplementary material, which is available to authorized users.
Highlights
TRFs, 14 to 32 nt long single-stranded RNA derived from mature or precursor tRNAs, are a recently discovered class of small RNA that have been found to be present in diverse organisms at read counts comparable to miRNAs
This study showed that tRNA-derived RNA fragment (tRF)-1s were formed by RNase Z as expected, tRF-3s and tRF-1s preferentially associated with Argonautes 3 and 4 over 1 and 2, tRF levels could affect the efficacy of miRNAs and small interfering RNA (siRNA), and a tRF-3 but not a tRF-1 could act in trans RNA silencing
We find that tRF-5s and tRF-3s, but not tRF-1s, are very abundant in AGO1, 3 and 4 photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) data and use canonical miRNA seed rules to associate with mRNAs
Summary
TRFs, 14 to 32 nt long single-stranded RNA derived from mature or precursor tRNAs, are a recently discovered class of small RNA that have been found to be present in diverse organisms at read counts comparable to miRNAs. First described in Escherichia coli as a response to bacteriophage infection [5], these fragments have been observed in numerous organisms and are commonly referred to as tiRNAs (reviewed in [6]) These molecules are known to accumulate during stress, are generated by Rny in yeast, angiogenin (ANG) in humans, and the 5’ halves have been shown to be capable of inhibiting protein translation in multiple organisms [7,8], while either the 5’ halves or 3’ halves could theoretically associate with RNase Z or RNase P, respectively, to slice target RNAs [9,10]. This study showed that tRF-1s were formed by RNase Z as expected, tRF-3s and tRF-1s preferentially associated with Argonautes 3 and 4 over 1 and 2, tRF levels could affect the efficacy of miRNAs and siRNAs, and a tRF-3 but not a tRF-1 could act in trans RNA silencing
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