title: Meta-Analysis of Multiple Sclerosis Microarray Data Reveals Dysregulation in RNA Splicing Regulatory Genes.
abstract: Abnormalities in RNA metabolism and alternative splicing (AS) are emerging as important players in complex disease phenotypes. In particular, accumulating evidence suggests the existence of pathogenic links between multiple sclerosis (MS) and altered AS, including functional studies showing that an imbalance in alternatively-spliced isoforms may contribute to disease etiology. Here, we tested whether the altered expression of AS-related genes represents a MS-specific signature. A comprehensive comparative analysis of gene expression profiles of publicly-available microarray datasets (190 MS cases, 182 controls), followed by gene-ontology enrichment analysis, highlighted a significant enrichment for differentially-expressed genes involved in RNA metabolism/AS. In detail, a total of 17 genes were found to be differentially expressed in MS in multiple datasets, with CELF1 being dysregulated in five out of seven studies. We confirmed CELF1 downregulation in MS (p=0.0015) by real-time RT-PCRs on RNA extracted from blood cells of 30 cases and 30 controls. As a proof of concept, we experimentally verified the unbalance in alternatively-spliced isoforms in MS of the NFAT5 gene, a putative CELF1 target. In conclusion, for the first time we provide evidence of a consistent dysregulation of splicing-related genes in MS and we discuss its possible implications in modulating specific AS events in MS susceptibility genes.
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, Milan 20133, Italy. elvezia.paraboschi@unimi.it.
authors.forename: Elvezia Maria
authors.initials: EM
authors.lastname: Paraboschi
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, Milan 20133, Italy. giulia.cardamone@studenti.unimi.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: Cardamone
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, Rozzano, Milan 20089, Italy. valeria.rimoldi@humanitasresearch.it.|Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, Milan 20089, Italy. valeria.rimoldi@humanitasresearch.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Rimoldi
authors.affiliation: Center Haemostasis & Thrombosis, Department of Medical Sciences, Corso Giovecca 203, University of Ferrara, Ferrara 44121, Italy. d.gemmati@unife.it.
authors.forename: Donato
authors.initials: D
authors.lastname: Gemmati
authors.affiliation: Department of Transfusion Medicine and Hematology, Azienda Ospedaliera della Provincia di Lecco, Alessandro Manzoni Hospital, Via dell'Eremo 9/11, Lecco 23900, Italy. ma.spreafico@ospedale.lecco.it.
authors.forename: Marta
authors.initials: M
authors.lastname: Spreafico
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, Rozzano, Milan 20089, Italy. stefano.duga@hunimed.eu.|Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, Milan 20089, Italy. stefano.duga@hunimed.eu.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, Rozzano, Milan 20089, Italy. giulia.solda@hunimed.eu.|Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, Milan 20089, Italy. giulia.solda@hunimed.eu.
authors.forename: Giulia
authors.initials: G
authors.lastname: Soldà
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, Rozzano, Milan 20089, Italy. rosanna.asselta@hunimed.eu.|Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, Milan 20089, Italy. rosanna.asselta@hunimed.eu.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
mesh_terms: D000368:Aged; D017398:Alternative Splicing / Q000235:genetics; D000067879:CELF1 Protein / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D005260:Female; D053263:Gene Regulatory Networks; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012984:Software
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; D012333:RNA, Messenger
keywords: alternative splicing; autoimmune neurodegenerative disorder; microarray; multiple sclerosis; peripheral blood mononuclear cells