Brain derived neurotrophic factor (BDNF) expression is regulated by microRNAs miR-26a and miR-26b allele-specific binding - PubMed (original) (raw)

Brain derived neurotrophic factor (BDNF) expression is regulated by microRNAs miR-26a and miR-26b allele-specific binding

Viviana Caputo et al. PLoS One. 2011.

Abstract

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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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Multiple genome alignment of BDNF 3′UTR in the region of polymorphic sites rs11030100 and rs11030099 (in bold letters).

Sequence analysis shows that sites are highly conserved among primate genomes.

Figure 2

Figure 2. Luciferase assays for validation of miR-26a and -26b binding to BDNF 3′UTR.

HeLa cells were independently transfected with control plasmid (pRL-TK) or each of the two reporter plasmid (pluc-BDNF C–G, anc, and pluc-BDNF A–T, der) with either miR-26a or miR-26b. Data are presented as the normalized activity of different reporter genes. Introduction of exogenous miR-26a and miR-26b represses reporter activity of pluc-BDNF C–G but has no effect on pluc-BDNF A–T. Data represent the mean of five independent experiments +SD (p<0.05).

Figure 3

Figure 3. Schematic representation of base pairing between miR-26a sequence and BDNF 3′UTR ancestral (C–G) and derivative (A–T) alleles of rs11030100 and rs11030099 polymorphic sites.

MiR-26b has the same seed binding sequence.

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