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Genome Res. 2017 Mar;27(3):374-384. doi: 10.1101/gr.208900.116. Epub 2017 Jan 13.

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

Roden C1,2,3,4, Gaillard J2,5, Kanoria S6, Rennie W6, Barish S4, Cheng J1,2,3, Pan W1,2,3, Liu J1,2,3, Cotsapas C1,7, Ding Y6, Lu J1,2,3,8.

Author information

1
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
2
Yale Stem Cell Center and Yale Cancer Center, Yale University, New Haven, Connecticut 06520, USA.
3
Yale Center for RNA Science and Medicine, New Haven, Connecticut 06520, USA.
4
Graduate Program in Biological and Biomedical Sciences, Yale University, New Haven, Connecticut 06510, USA.
5
School of Medicine, Yale University, New Haven, Connecticut 06510, USA.
6
Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA.
7
Department of Neurology, Yale School of Medicine, New Haven, Connecticut 06511, USA.
8
Yale Cooperative Center of Excellence in Hematology, Yale University, New Haven, Connecticut 06520, USA.

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.

PMID:
28087842
PMCID:
PMC5340965
[Available on 2017-09-01]
DOI:
10.1101/gr.208900.116
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