Abstract
RNA molecules generated by ribonuclease cleavage sometimes harbor a 2′,3′-cyclic phosphate (cP) at their 3′-ends. Those cP-containing RNAs (cP-RNAs) form a hidden layer of transcriptome because standard RNA-seq cannot capture them as a result of cP’s prevention of an adapter ligation reaction. Here we provide genome-wide analyses of short cP-RNA transcriptome across multiple mouse tissues. Using cP-RNA-seq that can exclusively sequence cP-RNAs, we identified numerous novel cP-RNA species which are mainly derived from cytoplasmic tRNAs, mRNAs, and rRNAs. Determination of the processing sites of substrate RNAs for cP-RNA generation revealed highly-specific RNA cleavage events between cytidine and adenosine in cP-RNA biogenesis. cP-RNAs were not evenly derived from the overall region of substrate RNAs but rather from specific sites, implying that cP-RNAs are not from random degradation but are produced through a regulated biogenesis pathway. The identified cP-RNAs were abundantly accumulated in mouse tissues, and the expression levels of cP-RNAs showed age-dependent reduction. These analyses of cP-RNA transcriptome unravel a novel, abundant class of non-coding RNAs whose expression could have physiological roles.
Highlights
Cells express immensely diverse species of RNA molecules that play essential roles in numerous biological processes
By using cyclic phosphate (cP)-RNA-seq technique that can sequence cPcontaining RNAs (cP-RNAs), we identified numerous novel cP-RNA species which are mainly derived from tRNAs, messenger RNAs (mRNAs), and ribosomal RNAs (rRNAs). cP-RNAs are generated by previously-uncharacterized, highlyspecific RNA cleavage events between cytidine and adenosine, which is regulated through aging
Because ANG-generated 50-tRNA halves contain a cP, exploration of the accumulation of cP-RNAs in mouse tissues began with analyses of tRNA halves
Summary
Cells express immensely diverse species of RNA molecules that play essential roles in numerous biological processes. A cP end of RNA molecules, consisting of the phosphate linkage between the 20- and 30-positions of ribose, is mainly produced from RNA cleavage catalyzed by many endoribonucleases [4]. Angiogenin (ANG), an RNase A-superfamily endoribonuclease, cleaves the anticodon-loop of tRNAs upon stress stimuli to produce functional tRNA halves known as tRNA-derived stress-induced RNAs (tiRNAs) [5]. In breast and prostate cancer cells, sex hormone signaling pathways promote ANG-catalyzed tRNA cleavages, generating a distinct class of tRNA halves, the sex hormone-dependent tRNA derived RNAs (SHOT-RNAs) [10]. CP-containing 50-SHOT-RNAs (50-tRNA halves) have a functional significance in cell proliferation [10,11] In breast and prostate cancer cells, sex hormone signaling pathways promote ANG-catalyzed tRNA cleavages, generating a distinct class of tRNA halves, the sex hormone-dependent tRNA derived RNAs (SHOT-RNAs) [10]. cP-containing 50-SHOT-RNAs (50-tRNA halves) have a functional significance in cell proliferation [10,11]
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