title: MicroRNA-511 Binds to FKBP5 mRNA, Which Encodes a Chaperone Protein, and Regulates Neuronal Differentiation.
abstract: Single nucleotide polymorphisms in the FKBP5 gene increase the expression of the FKBP51 protein and have been associated with increased risk for neuropsychiatric disorders such as major depression and post-traumatic stress disorder. Moreover, levels of FKBP51 are increased with aging and in Alzheimer disease, potentially contributing to disease pathogenesis. However, aside from its glucocorticoid responsiveness, little is known about what regulates FKBP5 In recent years, non-coding RNAs, and in particular microRNAs, have been shown to modulate disease-related genes and processes. The current study sought to investigate which miRNAs could target and functionally regulate FKBP5 Following in silico data mining and initial target expression validation, miR-511 was found to suppress FKBP5 mRNA and protein levels. Using luciferase p-miR-Report constructs and RNA pulldown assays, we confirmed that miR-511 bound directly to the 3'-UTR of FKBP5, validating the predicted gene-microRNA interaction. miR-511 suppressed glucocorticoid-induced up-regulation of FKBP51 in cells and primary neurons, demonstrating functional, disease-relevant control of the protein. Consistent with a regulator of FKBP5, miR-511 expression in the mouse brain decreased with age but increased following chronic glucocorticoid treatment. Analysis of the predicted target genes of miR-511 revealed that neurogenesis, neuronal development, and neuronal differentiation were likely controlled by these genes. Accordingly, miR-511 increased neuronal differentiation in cells and enhanced neuronal development in primary neurons. Collectively, these findings show that miR-511 is a functional regulator of FKBP5 and can contribute to neuronal differentiation.
authors.affiliation: From the Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida 33613.
authors.forename: Dali
authors.initials: D
authors.lastname: Zheng
authors.affiliation: From the Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida 33613.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Sabbagh
authors.affiliation: From the Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida 33613.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Blair
authors.affiliation: From the Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida 33613.
authors.forename: April L
authors.initials: AL
authors.lastname: Darling
authors.affiliation: From the Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida 33613.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Wen
authors.affiliation: From the Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida 33613 cdickey@health.usf.edu.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000096:biosynthesis* / Q000235:genetics; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D000099159:Tacrolimus Binding Protein 5
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D018832:Molecular Chaperones; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C578471:MIRN511 microRNA, human; C578472:Mirn511 microRNA, mouse
keywords: FKBP5; depression; glucocorticoid; microRNA (miRNA); neurodifferentiation; stress