title: Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains.
abstract: Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. Bioinformatic annotation has established that human chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA target pairs that may play a role, in part, in mediating the DS phenotype. We demonstrate by luciferase/target mRNA 3'-untranslated region reporter assays, and gain- and loss-of-function experiments that miR-155 and -802 can regulate the expression of the predicted mRNA target, the methyl-CpG-binding protein (MeCP2). We also demonstrate that MeCP2 is underexpressed in DS brain specimens isolated from either humans or mice. We further demonstrate that, as a consequence of attenuated MeCP2 expression, transcriptionally activated and silenced MeCP2 target genes, CREB1/Creb1 and MEF2C/Mef2c, are also aberrantly expressed in these DS brain specimens. Finally, in vivo silencing of endogenous miR-155 or -802, by antagomir intra-ventricular injection, resulted in the normalization of MeCP2 and MeCP2 target gene expression. Taken together, these results suggest that improper repression of MeCP2, secondary to trisomic overexpression of Hsa21-derived miRNAs, may contribute, in part, to the abnormalities in the neurochemistry observed in the brains of DS individuals. Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS.
authors.affiliation: College of Pharmacy, Division of Pharmacology, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kuhn
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
authors.forename: Mickey M
authors.initials: MM
authors.lastname: Martin
authors.forename: Geraldine E
authors.initials: GE
authors.lastname: Malana
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Sansom
authors.forename: Adam P
authors.initials: AP
authors.lastname: Pleister
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Beck
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.forename: David S
authors.initials: DS
authors.lastname: Feldman
authors.forename: Terry S
authors.initials: TS
authors.lastname: Elton
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D026161:MADS Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D064326:MEF2 Transcription Factors; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C115163:CREB1 protein, human; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D026161:MADS Domain Proteins; C497392:MECP2 protein, human; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; C497393:Mecp2 protein, mouse; C578041:Mef2c protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins