Human Molecular Genetics Advance Access published online on July 15, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn201
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A Set of Differentially Expressed miRNAs, including miR-30a-5p, act as Post-transcriptional Inhibitors of BDNF in Prefrontal Cortex
1 Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, Worcester, Massachusetts 2 University of Massachusetts Medical School, Graduate School of Biomedical Sciences, 303 Belmont Street, Worcester, Massachusetts 01604, USA
* To whom correspondence should be addressed at: Brudnick Neuropsychiatric Research Institute, 303 Belmont Street, Worcester, MA, 01604, USA. Email: schahram.akbarian{at}umassmed.edu. Tel.: 508-856-8204. Fax: 508-856-3937.
Received April 28, 2008; Revised July 10, 2008; Accepted July 10, 2008
Expression of Brain-Derived Neurotrophic Factor (BDNF) is developmentally regulated in prefrontal cortex (PFC). The underlying molecular mechanisms, however, remain unclear. Here, we explore the role of microRNAs (miRNAs) as post-transcriptional inhibitors of BDNF. A sequential approach involving in silico, miRNA microarray, in situ hybridization and qRT-PCR studies identified a group of 10 candidate miRNAs, segregating into 5 miRNA families (miR-30a-5p/b/c/d, miR-103/107, miR-191, miR-16/195, miR-495), which exhibited distinct developmental and lamina-specific expression in human PFC. Luciferase assays confirmed that at least two of these miRNAs, miR-30a-5p and miR-195, target specific sequences surrounding the proximal polyadenylation site within BDNF 3'UTR. Furthermore, neuronal overexpression of miR-30a-5p, a miRNA enriched in layer III pyramidal neurons, resulted in downregulation of BDNF protein. Notably, a subset of 7 miRNAs, including miR-30a-5p, exhibited an inverse correlation with BDNF protein levels in PFC of subjects age 15 to 84 years. In contrast, the role of transcriptional mechanisms was more apparent during the transition from fetal to childhood and/or young adult stages, when BDNF mRNA upregulation was accompanied by similar changes in (open chromatin-associated) histone H3-lysine 4 methylation at BDNF gene promoters I and IV. Collectively, our data highlight the multiple layers of regulation governing the developmental expression of BDNF in human PFC and suggest that miRNAs are involved in the fine-tuning of this neurotrophin particularly in adulthood.
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