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  • Gustafsson, MikaLinköpings universitet,Bioinformatik,Tekniska fakulteten,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden; Bioinformatics, Department of Physics, Chemistry, and Biology, Linköping University, Linköping, Sweden (author)

A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases

  • Article/chapterEnglish2015

Publisher, publication year, extent ...

  • AMER ASSOC ADVANCEMENT SCIENCE,2015
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-123522
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-123522URI
  • https://doi.org/10.1126/scitranslmed.aad2722DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-77098URI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:132482880URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding Agencies|Cancer fund, Swedish Medical Research Council [K2013-61X-22310-01-04, 2012-3168]; Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research [250114]; Sigrid Juselius Foundation; Generalitat de Catalunya AGAUR [2014-SGR364]; Spanish Association Against Cancer; Spanish Ministry of Health ISCIII FIS [PI12/01528]; RTICC [RD12/0036/0008]
  • Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.

Subject headings and genre

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  • Gawel, DanutaLinköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden(Swepub:liu)danga10 (author)
  • Alfredsson, LarsKarolinska Institutet (author)
  • Baranzini, SergioUniversity of Calif San Francisco, CA, USA,Department of Neurology, University of California, San Francisco, CA, USA (author)
  • Bjorkander, JanneFuturum-Academy for Health and Care, County Council of Jönköping, Jönköping, Sweden (author)
  • Blomgran, RobertLinköpings universitet,Avdelningen för mikrobiologi och molekylär medicin,Medicinska fakulteten,Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine, Linköping University, Linköping, Sweden(Swepub:liu)robbl96 (author)
  • Hellberg, SandraLinköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten,Department of Clinical and Experimental Medicine, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, Linköping, Sweden(Swepub:liu)sanhe13 (author)
  • Eklund, DanielLinköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten,Department of Clinical Immunology and Transfusion Medicine, Linköping University, Linköping, Sweden(Swepub:oru)ded (author)
  • Ernerudh, JanLinköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten,Region Östergötland, Klinisk immunologi och transfusionsmedicin,Department of Clinical and Experimental Medicine, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, Linköping, Sweden; Department of Clinical Immunology and Transfusion Medicine, Linköping University, Linköping, Sweden(Swepub:liu)janer15 (author)
  • Kockum, IngridKarolinska Institutet (author)
  • Konstantinell, AelitaLinköpings universitet,Medicinska fakulteten,Avdelningen för kliniska vetenskaper,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden; Department of Medical Biology, The Arctic University of Norway, Tromsø, Norway (author)
  • Lahesmaa, RiitaTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Lentini, AntonioLinköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden(Swepub:liu)antle32 (author)
  • Liljenström, H. Robert I.Linköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden (author)
  • Mattson, LinaLinköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden (author)
  • Matussek, AndreasFuturum-Academy for Health and Care, County Council of Jönköping, Jönköping, Sweden (author)
  • Mellergård, JohanLinköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten,Region Östergötland, Neurologiska kliniken i Linköping,Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden(Swepub:liu)johme15 (author)
  • Mendez, MelissaUniversity of Peruana Cayetano Heredia, Peru,Laboratorio de Investigación en Enfermedades Infecciosas, LID, Universidad Peruana Cayetano Heredia, Lima, Peru (author)
  • Olsson, TomasKarolinska Institutet (author)
  • Pujana, Miguel A.Catalan Institute Oncol, Spain,Program Against Cancer Therapeutic Resistance (ProCURE), Cancer and Systems Biology Unit, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain (author)
  • Rasool, OmidTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Serra-Musach, JordiCatalan Institute Oncol, Spain,Program Against Cancer Therapeutic Resistance (ProCURE), Cancer and Systems Biology Unit, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain (author)
  • Stenmarker, MargarethaFuturum-Academy for Health and Care, County Council of Jönköping, Jönköping, Sweden (author)
  • Tripathi, SubhashTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Viitala, MiroTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Wang, HuiLinköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,University of Texas MD Anderson Cancer Centre, TX 77030 USA,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden; Department of Immunology, MD Anderson Cancer Center, Houston, TX, USA(Swepub:liu)huiwa84 (author)
  • Zhang, HuanLinköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden(Swepub:liu)huazh47 (author)
  • Nestor, ColmLinköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden(Swepub:liu)colne37 (author)
  • Benson, MikaelLinköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,Region Östergötland, Allergicentrum US,The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden(Swepub:liu)mikbe05 (author)
  • Linköpings universitetBioinformatik (creator_code:org_t)

Related titles

  • In:Science Translational Medicine: AMER ASSOC ADVANCEMENT SCIENCE7:3131946-62341946-6242

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