title: Genome-wide miR-155 and miR-802 target gene identification in the hippocampus of Ts65Dn Down syndrome mouse model by miRNA sponges.
abstract: BACKGROUND
  Down syndrome (DS) or trisomy 21 is the result of a genetic dosage imbalance that translates in a broad clinical spectrum. A major challenge in the study of DS is the identification of functional genetic elements with wide impact on phenotypic alterations. Recently, miRNAs have been recognized as major contributors to several disease conditions by acting as post-transcriptional regulators of a plethora of genes. Five chromosome 21 (HSA21) miRNAs have been found overexpressed in DS individuals and could function as key elements in the pathophysiology. Interestingly, in the trisomic Ts65Dn DS mouse model two of these miRNAs (miR-155 and miR-802) are also triplicated and overexpressed in brain.
  
  
  RESULTS
  In the current work, we interrogated the impact of miR-155 and miR-802 upregulation on the transcriptome of Ts65Dn brains. We developed a lentiviral miRNA-sponge strategy (Lv-miR155-802T) to identify in vivo relevant miR-155 and miR-802 target mRNAs. Hippocampal injections of lentiviral sponges in Ts65Dn mice normalized the expression of miR-155 and miR-802 and rescued the levels of their targets methyl-CpG-binding protein 2 gene (Mecp2), SH2 (Src homology 2)-containing inositol phosphatase-1 (Ship1) and Forkhead box protein M1 (FoxM1). Transcriptomic data of Lv-miR155-802T miRNA-sponge treated hippocampi correlated with candidate targets highlighting miRNA dosage-sensitive genes. Significant associations were found in a subset of genes (Rufy2, Nova1, Nav1, Thoc1 and Sumo3) that could be experimentally validated.
  
  
  CONCLUSIONS
  The lentiviral miRNA-sponge strategy demonstrated the genome-wide regulatory effects of miR-155 and miR-802. Furthermore, the analysis combining predicted candidates and experimental transcriptomic data proved to retrieve genes with potential significance in DS-hippocampal phenotype bridging with DS other neurological-associated diseases such as Alzheimer's disease.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bofill-De Ros
authors.affiliation: Bioinformatics Platform, CIBERehd, Barcelona, Spain.|Present address: Institute of Biology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Mónica
authors.initials: M
authors.lastname: Santos
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain.|Bioinformatics Platform, CIBERehd, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Vila-Casadesús
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain.
authors.forename: Eneko
authors.initials: E
authors.lastname: Villanueva
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Bioinformatics Platform, CIBERehd, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Andreu
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Cellular and Systems Neurobiology, Systems Biology Programme, Centre for Genomic Regulation (CRG), Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain. cfillat@clinic.ub.es.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. cfillat@clinic.ub.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
mesh_terms: D000818:Animals; D002460:Cell Line; D004314:Down Syndrome / Q000235:genetics*; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D035683:MicroRNAs