Single nucleotide polymorphisms affect RNA-protein interactions at a distance through modulation of RNA secondary structures
Single nucleotide polymorphisms affect RNA-protein interactions at a distance through modulation of RNA secondary structures
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DOI：
10.1371/journal.pcbi.1007852
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发表时间：
2020-05-01
影响因子：
4.3
通讯作者：
Bundschuh, Ralf
中科院分区：
文献类型：
--
作者：
Shatoff, Elan;Bundschuh, Ralf
单核苷酸多态性与疾病广泛相关，但它们导致表型改变的方式通常不清楚，特别是当它们出现在非编码区时。非编码多态性可能导致疾病的一种方式是影响关键的RNA-蛋白质相互作用。虽然很明显，改变蛋白质结合基序将改变蛋白质结合，它已被证明，单核苷酸多态性可以影响RNA二级结构，在这里，我们表明，单核苷酸多态性可以影响RNA-蛋白质相互作用从外部结合基序通过改变RNA二级结构。通过使用人类HuR（ELAVL 1）的维也纳软件包和PAR-CLIP数据的修改版本，我们表征了单核苷酸多态性对HuR结合的全基因组效应，并表明它们可以对HuR结合数十个碱基的RNA转录物的亲和力产生多倍影响。我们还发现一些证据表明，单核苷酸多态性对蛋白质结合的影响可能是在选择，与非参考等位基因往往使其更难为一个蛋白质bind.Author summarySingle核苷酸多态性是一个基因组中的单核苷酸，不同的子集之间的人口。已知它们会引起许多疾病，但它们引起疾病的方式往往是未知的。我们发现单核苷酸多态性可能导致疾病的一种方式是改变RNA分子的折叠方式。RNA分子中的核苷酸可以彼此碱基配对以形成复杂的结构。这种结构决定了一些蛋白质可以结合的位置，因为许多蛋白质只能结合单链RNA。如果由单核苷酸多态性引起的从一个碱基到另一个碱基的变化导致蛋白质结合基序变得优先碱基配对，那么蛋白质将更难在那里结合。通过模拟RNA的折叠与蛋白质结合，我们表明单核苷酸多态性可以影响特定蛋白质与RNA结合的能力，通常使蛋白质更难结合。
Single nucleotide polymorphisms are widely associated with disease, but the ways in which they cause altered phenotypes are often unclear, especially when they appear in non-coding regions. One way in which non-coding polymorphisms could cause disease is by affecting crucial RNA-protein interactions. While it is clear that changing a protein binding motif will alter protein binding, it has been shown that single nucleotide polymorphisms can affect RNA secondary structure, and here we show that single nucleotide polymorphisms can affect RNA-protein interactions from outside binding motifs through altered RNA secondary structure. By using a modified version of the Vienna Package and PAR-CLIP data for HuR (ELAVL1) in humans we characterize the genome-wide effect of single nucleotide polymorphisms on HuR binding and show that they can have a many-fold effect on the affinity of HuR binding to RNA transcripts from tens of bases away. We also find some evidence that the effect of single nucleotide polymorphisms on protein binding might be under selection, with the non-reference alleles tending to make it harder for a protein to bind.Author summarySingle nucleotide polymorphisms are single nucleotides in a genome that vary between subsets of a population. They are known to cause many diseases, but the ways in which they cause disease are often unknown. We show that one way in which single nucleotide polymorphisms may cause disease is by altering how RNA molecules fold. The nucleotides in an RNA molecule can base pair to each other to form complicated structures. This structure dictates where some proteins can bind, since many proteins can only bind to single stranded RNA. If the change from one base to another base caused by a single nucleotide polymorphism causes a protein binding motif to become preferentially base paired, then it will be harder for a protein to bind there. By modelling the folding of RNAs in conjunction with protein binding in silico, we show that single nucleotide polymorphisms can affect the ability of specific proteins to bind to RNAs, usually making it harder for proteins to bind.