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Novel determinants of mammalian primary microRNA processing revealed by systematic evaluation of hairpin-containing transcripts and human genetic variation

    • 1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
    • 2Yale Stem Cell Center and Yale Cancer Center, Yale University, New Haven, Connecticut 06520, USA;
    • 3Yale Center for RNA Science and Medicine, New Haven, Connecticut 06520, USA;
    • 4Graduate Program in Biological and Biomedical Sciences, Yale University, New Haven, Connecticut 06510, USA;
    • 5School of Medicine, Yale University, New Haven, Connecticut 06510, USA;
    • 6Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA;
    • 7Department of Neurology, Yale School of Medicine, New Haven, Connecticut 06511, USA;
    • 8Yale Cooperative Center of Excellence in Hematology, Yale University, New Haven, Connecticut 06520, USA
    • 9 These authors contributed equally to this work.
Published January 13, 2017. Vol 27 Issue 3, pp. 374-384. https://doi.org/10.1101/gr.208900.116
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Abstract

Mature microRNAs (miRNAs) are processed from hairpin-containing primary miRNAs (pri-miRNAs). However, rules that distinguish pri-miRNAs from other hairpin-containing transcripts in the genome are incompletely understood. By developing a computational pipeline to systematically evaluate 30 structural and sequence features of mammalian RNA hairpins, we report several new rules that are preferentially utilized in miRNA hairpins and govern efficient pri-miRNA processing. We propose that a hairpin stem length of 36 ± 3 nt is optimal for pri-miRNA processing. We identify two bulge-depleted regions on the miRNA stem, located ∼16–21 nt and ∼28–32 nt from the base of the stem, that are less tolerant of unpaired bases. We further show that the CNNC primary sequence motif selectively enhances the processing of optimal-length hairpins. We predict that a small but significant fraction of human single-nucleotide polymorphisms (SNPs) alter pri-miRNA processing, and confirm several predictions experimentally including a disease-causing mutation. Our study enhances the rules governing mammalian pri-miRNA processing and suggests a diverse impact of human genetic variation on miRNA biogenesis.

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