title: Identification of ncRNAs as potential therapeutic targets in multiple sclerosis through differential ncRNA - mRNA network analysis.
abstract: BACKGROUND
  Several studies have revealed a potential role for both small nucleolar RNAs (snoRNAs) and microRNAs (miRNAs) in the physiopathology of relapsing-remitting multiple sclerosis (RRMS). This potential implication has been mainly described through differential expression studies. However, it has been suggested that, in order to extract additional information from large-scale expression experiments, differential expression studies must be complemented with differential network studies. Thus, the present work is aimed at the identification of potential therapeutic ncRNA targets for RRMS through differential network analysis of ncRNA - mRNA coexpression networks. ncRNA - mRNA coexpression networks have been constructed from both selected ncRNA (specifically miRNAs, snoRNAs and sdRNAs) and mRNA large-scale expression data obtained from 22 patients in relapse, the same 22 patients in remission and 22 healthy controls. Condition-specific (relapse, remission and healthy) networks have been built and compared to identify the parts of the system most affected by perturbation and aid the identification of potential therapeutic targets among the ncRNAs.
  
  
  RESULTS
  All the coexpression networks we built present a scale-free topology and many snoRNAs are shown to have a prominent role in their architecture. The differential network analysis (relapse vs. remission vs. controls' networks) has revealed that, although both network topology and the majority of the genes are maintained, few ncRNA - mRNA links appear in more than one network. We have selected as potential therapeutic targets the ncRNAs that appear in the disease-specific network and were found to be differentially expressed in a previous study.
  
  
  CONCLUSIONS
  Our results suggest that the diseased state of RRMS has a strong impact on the ncRNA - mRNA network of peripheral blood leukocytes, as a massive rewiring of the network happens between conditions. Our findings also indicate that the role snoRNAs have in targeted gene silencing is a widespread phenomenon. Finally, among the potential therapeutic target ncRNAs, SNORA40 seems to be the most promising candidate.
authors.affiliation: Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain. haritz.irizar@biodonostia.org.|Spanish Network on Multiple Sclerosis (REEM), San Sebastián, Spain. haritz.irizar@biodonostia.org.
authors.forename: Haritz
authors.initials: H
authors.lastname: Irizar
authors.affiliation: Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain. maider.munoz@biodonostia.org.|Spanish Network on Multiple Sclerosis (REEM), San Sebastián, Spain. maider.munoz@biodonostia.org.
authors.forename: Maider
authors.initials: M
authors.lastname: Muñoz-Culla
authors.affiliation: Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain. matias.saenz@biodonostia.org.|Spanish Network on Multiple Sclerosis (REEM) and Immunology Department, Donostia University Hospital, San Sebastián, Spain. matias.saenz@biodonostia.org.
authors.forename: Matías
authors.initials: M
authors.lastname: Sáenz-Cuesta
authors.affiliation: Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain. inaki.osorio@biodonostia.org.|Spanish Network on Multiple Sclerosis (REEM), San Sebastián, Spain. inaki.osorio@biodonostia.org.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Osorio-Querejeta
authors.affiliation: Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain. lucia.sepulveda@biodonostia.org.|Spanish Network on Multiple Sclerosis (REEM), San Sebastián, Spain. lucia.sepulveda@biodonostia.org.
authors.forename: Lucía
authors.initials: L
authors.lastname: Sepúlveda
authors.affiliation: Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain. tamara.castillotrivino@osakidetza.net.|Spanish Network on Multiple Sclerosis (REEM) and Neurology Department, Donostia University Hospital, San Sebastián, Spain. tamara.castillotrivino@osakidetza.net.
authors.forename: Tamara
authors.initials: T
authors.lastname: Castillo-Triviño
authors.affiliation: Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain. alvarojose.pradainurrategi@biodonostia.org.|Immunology Department, Donostia University Hospital, San Sebastián, Spain. alvarojose.pradainurrategi@biodonostia.org.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Prada
authors.affiliation: Biodonostia Health Research Institute, San Sebastián, Spain. Spainadolfojose.lopezdemunainarregui@osakidetza.net.|Department of Neurology, Donostia University Hospital, Donostia - San Sebastián, Spain. Spainadolfojose.lopezdemunainarregui@osakidetza.net.|Centro de Investigación Biomédica en red Enfermedades Neurodegenerativas (CIBERNED) and Department of Neuroscience, University of the Basque Country (UVP/EHU), San Sebastián, Spain. Spainadolfojose.lopezdemunainarregui@osakidetza.net.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Lopez de Munain
authors.affiliation: Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain. javier.olascoagaurtaza@osakidetza.net.|Spanish Network on Multiple Sclerosis (REEM) and Neurology Department, Donostia University Hospital, San Sebastián, Spain. javier.olascoagaurtaza@osakidetza.net.
authors.forename: Javier
authors.initials: J
authors.lastname: Olascoaga
authors.affiliation: Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain. david.otaegui@biodonostia.org.|Spanish Network on Multiple Sclerosis (REEM), San Sebastián, Spain. david.otaegui@biodonostia.org.
authors.forename: David
authors.initials: D
authors.lastname: Otaegui
mesh_terms: D000328:Adult; D005260:Female; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism*; D020537:RNA, Small Nucleolar / Q000378:metabolism; D022661:RNA, Untranslated / Q000378:metabolism*; D012008:Recurrence
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D020537:RNA, Small Nucleolar; D022661:RNA, Untranslated