Brain derived neurotrophic factor (BDNF) expression is regulated by microRNAs miR-26a and miR-26b allele-specific binding.
Brain derived neurotrophic factor (BDNF) expression is regulated by microRNAs miR-26a and miR-26b allele-specific binding.
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DOI：
10.1371/journal.pone.0028656
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Pizzuti A
中科院分区：
文献类型：
--
作者：
Caputo V;Sinibaldi L;Fiorentino A;Parisi C;Catalanotto C;Pasini A;Cogoni C;Pizzuti A
脑源性神经营养因子（BDNF）是一种神经营养因子，在神经元发育和可塑性中起重要作用。microRNA（miRNAs）是一类长度约为22个核苷酸的非编码小RNA，在转录后水平调控基因表达。本研究探讨了miRNAs作为BDNF转录后抑制因子的作用以及3′UTR序列变异对miRNAs结合能力的影响。利用计算机模拟的方法，我们鉴定了一组调控BDNF表达并与BDNF 3′UTR多态性序列结合的miRNA。荧光素酶分析表明，这些miRNAs（miR-26 a1/2和miR-26 b）下调BDNF的表达，并在BDNF 3′UTR定位的两个单核苷酸多态性（rs 11030100和rs 11030099）的变异等位基因的存在，特异性地废除了miRNAs的靶向。此外，我们还发现rs 11030099和rs6265（Val 66 Met）之间存在高度的连锁不平衡率，rs 11030100和rs6265（Val 66 Met）调节BDNF mRNA的定位和蛋白质的细胞内运输。这样的观察导致假设miR-26 s介导的调节可以延伸到rs6265，导致等位基因不平衡，具有潜在的功能效应，例如肽的定位和活性依赖性分泌。由于rs6265以前已被牵连在各种神经精神疾病，我们评估了rs 11030100，rs 11030099和rs6265的分布在对照组和精神分裂症组，但没有显着差异的等位基因频率出现。总之，在本研究中，我们鉴定了两种新的调节BDNF表达的miRNAs和第一个改变miRNA-BDNF结合的BDNF 3′UTR功能变体。
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3′UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3′UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3′UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptide's localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3′UTR functional variants altering miRNAs-BDNF binding.
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大脑表达的microRNA与精神分裂症病因有关。
影响因子：
3.7
作者：
Hansen, Thomas;Olsen, Line;Lindow, Morten;Jakobsen, Klaus D.;Ullum, Henrik;Jonsson, Erik;Andreassen, Ole A.;Djurovic, Srdjan;Melle, Ingrid;Agartz, Ingrid;Hall, Hakan;Timm, Sally;Wang, August G.;Werge, Thomas
通讯作者：
Werge, Thomas
DOI：
10.1073/pnas.0902833106
发表时间：
2009-09-22
影响因子：
11.1
作者：
Chiaruttini, C.;Vicario, A.;Tongiorgi, E.
通讯作者：
Tongiorgi, E.
影响因子：
2.6
作者：
Excoffier, Laurent;Laval, Guillaume;Schneider, Stefan
通讯作者：
Schneider, Stefan
影响因子：
14.9
作者：
Bao L;Zhou M;Wu L;Lu L;Goldowitz D;Williams RW;Cui Y
通讯作者：
Cui Y
DOI：
10.1073/pnas.0812446106
发表时间：
2009-05-12
影响因子：
11.1
作者：
Friedman, Lilach M.;Dror, Amiel A.;Avraham, Karen B.
通讯作者：
Avraham, Karen B.