Novel determinants of mammalian primary microRNA processing revealed by systematic evaluation of hairpin-containing transcripts and human genetic variation.
Novel determinants of mammalian primary microRNA processing revealed by systematic evaluation of hairpin-containing transcripts and human genetic variation.
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DOI：
10.1101/gr.208900.116
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发表时间：
2017-03
期刊：
影响因子：
7
通讯作者：
Lu J
中科院分区：
文献类型：
--
作者：
Roden C;Gaillard J;Kanoria S;Rennie W;Barish S;Cheng J;Pan W;Liu J;Cotsapas C;Ding Y;Lu J
成熟的microrna （mirna）是由含有发夹的初级microrna （pri-miRNAs）加工而成的。然而，区分pri- mirna与基因组中其他含有发夹的转录本的规则尚不完全清楚。通过开发一个计算管道来系统地评估哺乳动物RNA发夹的30个结构和序列特征，我们报告了一些优先用于miRNA发夹并控制有效的pri-miRNA加工的新规则。我们建议发夹茎长度为36±3 nt是pri-miRNA加工的最佳长度。我们在miRNA茎上发现了两个凸起缺失的区域，分别位于茎基部~ 16-21 nt和~ 28-32 nt处，它们对未配对的碱基的耐受性较差。我们进一步证明CNNC一级序列基序选择性地增强了最优长度发卡的加工。我们预测一小部分但重要的人类单核苷酸多态性（snp）会改变pri-miRNA的加工，并通过实验证实了一些预测，包括致病突变。我们的研究增强了哺乳动物pri-miRNA加工的规则，并表明人类遗传变异对miRNA生物发生的多种影响。
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.