Genome-wide miR-155 and miR-802 target gene identification in the hippocampus of Ts65Dn Down syndrome mouse model by miRNA sponges

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• dc.contributor.author Bofill-De Ros, Xavierca
• dc.contributor.author Santos, Mónicaca
• dc.contributor.author Vila-Casadesús, Mariaca
• dc.contributor.author Villanueva, Enekoca
• dc.contributor.author Andreu Somavilla, Núriaca
• dc.contributor.author Dierssen, Maraca
• dc.contributor.author Fillat i Fonts, Cristinaca
• dc.date.accessioned 2015-11-18T14:15:03Z
• dc.date.available 2015-11-18T14:15:03Z
• dc.date.issued 2015ca
• dc.description.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./nResults. 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./nConclusions. 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.
• dc.description.sponsorship This work was supported by grants from Jérôme Lejeune Foundation, Fundació Catalana Síndrome de Down, the Spanish Ministry of Economía y Competitividad BIO2011-30299-C02-02, BIO2014-57716-C2-2-R and SAF2013-49129-C2-1-R, Era Net Neuron Food-for-Thought (PCIN-2013-060), and received partial support from Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (SGR14/248 and SGR14/1125). CIBERER is an initiative of the ISCIII. CF group is partially financed by ISCIII (IIS10/00014) and co-financed by Fondo Europeo de Desarrollo Regional (FEDER). We acknowledge support from the Spanish Ministry, ‘Centro de Excelencia Severo Ochoa 2013-2017’, SEV-2012-0208. X. Bofill-De Ros and M. Vila were recipients of a FPU fellowship from the Spanish Ministry of Education. E. Villanueva was supported by a fellowship from the Gobierno Vasco, Spain. This work was developed at the Centre Esther Koplowitz, Barcelona, Spain.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Bofill-De Ros X, Santos M, Vila-Casadesús M, Villanueva E, Andreu N, Dierssen M, Fillat C. Genome-wide miR-155 and miR-802 target gene identification in the hippocampus of Ts65Dn Down syndrome mouse model by miRNA sponges. BMC Genomics. 2015;16:907. DOI: 0.1186/s12864-015-2160-6ca
• dc.identifier.doi http://dx.doi.org/10.1186/s12864-015-2160-6
• dc.identifier.issn 1471-2164ca
• dc.identifier.uri http://hdl.handle.net/10230/25139
• dc.language.iso engca
• dc.publisher BioMed Centralca
• dc.relation.ispartof BMC Genomics. 2015;16:907
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BIO2011-30299-C02
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2014-57716-C2
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-49129-C2
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SEV2012-0208
• dc.rights © 2015 Bofill-De Ros et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword miRNAs
• dc.subject.keyword Transcriptome
• dc.subject.keyword Sponges
• dc.subject.keyword Down syndrome
• dc.subject.other Down, Síndrome de
• dc.title Genome-wide miR-155 and miR-802 target gene identification in the hippocampus of Ts65Dn Down syndrome mouse model by miRNA spongesca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca