The Typical tRNA Co-Expresses Multiple 5′ tRNA Halves Whose Sequences and Abundances Depend on Isodecoder and Isoacceptor and Change with Tissue Type, Cell Type, and Disease

Transfer RNA-derived fragments (tRFs) are noncoding RNAs that arise from either mature transfer RNAs (tRNAs) or their precursors. One important category of tRFs comprises the tRNA halves, which are generated through cleavage at the anticodon. A given tRNA typically gives rise to several co-expressed 5'-tRNA halves (5 '-tRHs) that differ in the location of their 3 ' ends. These 5 '-tRHs, even though distinct, have traditionally been treated as indistinguishable from one another due to their near-identical sequences and lengths. We focused on co-expressed 5 '-tRHs that arise from the same tRNA and systematically examined their exact sequences and abundances across 10 different human tissues. To this end, we manually curated and analyzed several hundred human RNA-seq datasets from NCBI's Sequence Run Archive (SRA). We grouped datasets from the same tissue into their own collection and examined each group separately. We found that a given tRNA produces different groups of co-expressed 5 '-tRHs in different tissues, different cell lines, and different diseases. Importantly, the co-expressed 5 '-tRHs differ in their sequences, absolute abundances, and relative abundances, even among tRNAs with near-identical sequences from the same isodecoder or isoacceptor group. The findings suggest that co-expressed 5 '-tRHs that are produced from the same tRNA or closely related tRNAs have distinct, context-dependent roles. Moreover, our analyses show that cell lines modeling the same tissue type and disease may not be interchangeable when it comes to experimenting with tRFs.