LETTER

Mouse let-7 miRNA populations exhibit RNA editing that is constrained in the 5′-seed/ cleavage/anchor regions and stabilize predicted mmu-let-7a:mRNA duplexes

    • 1 Department of Chemistry, University of Houston, Houston, Texas 77204, USA;
    • 2 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
    • 3 Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA;
    • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA;
    • 5 Diabetes Center, University of California, San Francisco, California 94143, USA;
    • 6 Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA;
    • 7 Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA;
    • 8 Department of Physics, University of Houston, Houston, Texas 77204, USA;
    • 9 Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA;
    • 10 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    • 11 These authors contributed equally to this work.
    • 12 These authors contributed equally to this work.
    • 13 Corresponding author. E-mail [email protected]; fax (713) 743-2636.
Published July 9, 2008. Vol 18 Issue 10, pp. 1571-1581. https://doi.org/10.1101/gr.078246.108
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Abstract

Massively parallel sequencing of millions of <30-nt RNAs expressed in mouse ovary, embryonic pancreas (E14.5), and insulin-secreting beta-cells (βTC-3) reveals that ∼50% of the mature miRNAs representing mostly the mmu-let-7 family display internal insertion/deletions and substitutions when compared to precursor miRNA and the mouse genome reference sequences. Approximately, 12%–20% of species associated with mmu-let-7 populations exhibit sequence discrepancies that are dramatically reduced in nucleotides 3–7 (5′-seed) and 10–15 (cleavage and anchor sites). This observation is inconsistent with sequencing error and leads us to propose that the changes arise predominantly from post-transcriptional RNA-editing activity operating on miRNA:target mRNA complexes. Internal nucleotide modifications are most enriched at the ninth nucleotide position. A common ninth base edit of U-to-G results in a significant increase in stability of down-regulated let-7a targets in inhibin-deficient mice (Inha−/−). An excess of U-insertions (14.8%) over U-deletions (1.5%) and the presence of cleaved intermediates suggest that a mammalian TUTase (terminal uridylyl transferase) mediated dUTP-dependent U-insertion/U-deletion cycle may be a possible mechanism. We speculate that mRNA target site-directed editing of mmu-let-7a duplex-bulges stabilizes “loose” miRNA:mRNA target associations and functions to expand the target repertoire and/or enhance mRNA decay over translational repression. Our results also demonstrate that the systematic study of sequence variation within specific RNA classes in a given cell type from millions of sequences generated by next-generation sequencing (NGS) technologies (“intranomics”) can be used broadly to infer functional constraints on specific parts of completely uncharacterized RNAs.

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