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NF90 调节一组人类前体 miRNA 的加工。

NF90 modulates processing of a subset of human pri-miRNAs.

机构信息

UMR9002 CNRS-UM, Institut de Génétique Humaine-Université de Montpellier, Gene Regulation lab, Montpellier 34396, France.

Laboratory of Molecular Biology, Science Research Centre, Kochi Medical School, Kochi University, Kochi 783-8505, Japan.

出版信息

Nucleic Acids Res. 2020 Jul 9;48(12):6874-6888. doi: 10.1093/nar/gkaa386.

DOI:10.1093/nar/gkaa386
PMID:32427329
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7337520/
Abstract

MicroRNAs (miRNAs) are predicted to regulate the expression of >60% of mammalian genes and play fundamental roles in most biological processes. Deregulation of miRNA expression is a hallmark of most cancers and further investigation of mechanisms controlling miRNA biogenesis is needed. The double stranded RNA-binding protein, NF90 has been shown to act as a competitor of Microprocessor for a limited number of primary miRNAs (pri-miRNAs). Here, we show that NF90 has a more widespread effect on pri-miRNA biogenesis than previously thought. Genome-wide approaches revealed that NF90 is associated with the stem region of 38 pri-miRNAs, in a manner that is largely exclusive of Microprocessor. Following loss of NF90, 22 NF90-bound pri-miRNAs showed increased abundance of mature miRNA products. NF90-targeted pri-miRNAs are highly stable, having a lower free energy and fewer mismatches compared to all pri-miRNAs. Mutations leading to less stable structures reduced NF90 binding while increasing pri-miRNA stability led to acquisition of NF90 association, as determined by RNA electrophoretic mobility shift assay (EMSA). NF90-bound and downregulated pri-miRNAs are embedded in introns of host genes and expression of several host genes is concomitantly reduced. These data suggest that NF90 controls the processing of a subset of highly stable, intronic miRNAs.

摘要

微小 RNA（miRNAs）被预测能调控超过 60%的哺乳动物基因的表达，并在大多数生物过程中发挥着基本作用。miRNA 表达的失调是大多数癌症的一个特征，因此需要进一步研究控制 miRNA 生物发生的机制。双链 RNA 结合蛋白 NF90 已被证明可以作为 Microprocessor 的一种竞争性物质，用于有限数量的初级 miRNA（pri-miRNAs）。在这里，我们发现 NF90 对 pri-miRNA 生物发生的影响比之前认为的要广泛得多。全基因组方法显示，NF90 与 38 个 pri-miRNA 的茎区以一种很大程度上与 Microprocessor 不同的方式相关联。在 NF90 缺失后，22 个 NF90 结合的 pri-miRNA 显示出成熟 miRNA 产物的丰度增加。NF90 靶向的 pri-miRNAs 高度稳定，与所有 pri-miRNAs 相比，具有更低的自由能和更少的错配。导致结构稳定性降低的突变减少了 NF90 的结合，而增加 pri-miRNA 的稳定性则导致 NF90 的结合，这是通过 RNA 电泳迁移率变动分析（EMSA）确定的。NF90 结合和下调的 pri-miRNAs 嵌入在宿主基因的内含子中，并且几个宿主基因的表达同时降低。这些数据表明，NF90 控制着一组高度稳定、内含子 miRNA 的加工。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/095ea995aadf/gkaa386fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/4e87f4c5166e/gkaa386fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/53a47fd9af60/gkaa386fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/95dcacc68ddf/gkaa386fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/bd2fa9e33e40/gkaa386fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/8ee3a0e6fbaa/gkaa386fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/f2e4e41d3b86/gkaa386fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/4b50ddf81ba8/gkaa386fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/095ea995aadf/gkaa386fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/4e87f4c5166e/gkaa386fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/53a47fd9af60/gkaa386fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/95dcacc68ddf/gkaa386fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/bd2fa9e33e40/gkaa386fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/8ee3a0e6fbaa/gkaa386fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/f2e4e41d3b86/gkaa386fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/4b50ddf81ba8/gkaa386fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/489b/7337520/095ea995aadf/gkaa386fig8.jpg

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