Evidence for natural antisense transcript-mediated inhibition of microRNA function.
Evidence for natural antisense transcript-mediated inhibition of microRNA function.
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DOI：
10.1186/gb-2010-11-5-r56
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发表时间：
2010
期刊：
影响因子：
12.3
通讯作者：
Wahlestedt C
中科院分区：
文献类型：
--
作者：
Faghihi MA;Zhang M;Huang J;Modarresi F;Van der Brug MP;Nalls MA;Cookson MR;St-Laurent G 3rd;Wahlestedt C
microRNA（miRNAs）具有调节多种mRNA靶点的潜力。此外，哺乳动物基因组含有许多天然反义转录物，其中大多数似乎是非蛋白编码RNA（ncRNA）。我们最近发现并鉴定了一个高度保守的β-分泌酶-1（BACE 1）的非编码反义转录物，BACE 1是阿尔茨海默病病理生理学中的关键酶。BACE 1反义转录物在阿尔茨海默病患者的脑样品中显著上调，并促进（正义）BACE 1转录物的稳定性。我们在这里报告，BACE 1反义通过掩蔽miR-485- 5 p的结合位点来防止miRNA诱导的BACE 1 mRNA的抑制。事实上，miR-485- 5 p和BACE 1-反义在BACE 1 mRNA的开放阅读框中的相同区域内竞争结合。我们在体外观察了BACE 1反义和miR-485- 5 p对BACE 1蛋白的相反作用，并表明锁核酸-antimiR介导的miR-485- 5 p敲低以及BACE 1反义过表达可以防止miRNA诱导的BACE 1抑制。我们发现，与对照个体相比，阿尔茨海默病受试者的RNA样本中BACE 1-反义以及miR-485- 5 p的表达失调。我们的数据表明，在BACE 1基因表达的计算中，两组不同的调控RNA之间存在界面。此外，生物信息学分析揭示了天然反义转录物与miRNA在后者结合位点上的许多其他潜在相互作用的理论基础。
MicroRNAs (miRNAs) have the potential to regulate diverse sets of mRNA targets. In addition, mammalian genomes contain numerous natural antisense transcripts, most of which appear to be non-protein-coding RNAs (ncRNAs). We have recently identified and characterized a highly conserved non-coding antisense transcript for beta-secretase-1 (BACE1), a critical enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript is markedly up-regulated in brain samples from Alzheimer's disease patients and promotes the stability of the (sense) BACE1 transcript. We report here that BACE1-antisense prevents miRNA-induced repression of BACE1 mRNA by masking the binding site for miR-485-5p. Indeed, miR-485-5p and BACE1-antisense compete for binding within the same region in the open reading frame of the BACE1 mRNA. We observed opposing effects of BACE1-antisense and miR-485-5p on BACE1 protein in vitro and showed that Locked Nucleic Acid-antimiR mediated knockdown of miR-485-5p as well as BACE1-antisense over-expression can prevent the miRNA-induced BACE1 suppression. We found that the expression of BACE1-antisense as well as miR-485-5p are dysregulated in RNA samples from Alzheimer's disease subjects compared to control individuals. Our data demonstrate an interface between two distinct groups of regulatory RNAs in the computation of BACE1 gene expression. Moreover, bioinformatics analyses revealed a theoretical basis for many other potential interactions between natural antisense transcripts and miRNAs at the binding sites of the latter.
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