title: A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases.
abstract: 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.
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden. Bioinformatics, Department of Physics, Chemistry, and Biology, Linköping University, SE-581 83 Linköping, Sweden. mika.gustafsson@liu.se mikael.benson@liu.se.
authors.forename: Mika
authors.initials: M
authors.lastname: Gustafsson
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Danuta R
authors.initials: DR
authors.lastname: Gawel
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Solna, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Baranzini
authors.affiliation: Futurum-Academy for Health and Care, County Council of Jönköping, SE-551 85 Jönköping, Sweden.
authors.forename: Janne
authors.initials: J
authors.lastname: Björkander
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Blomgran
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hellberg
authors.affiliation: Department of Clinical Immunology and Transfusion Medicine, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eklund
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, SE-581 83 Linköping, Sweden. Department of Clinical Immunology and Transfusion Medicine, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Ernerudh
authors.affiliation: Department of Clinical Neurosciences, Karolinska Institutet and Centrum for Molecular Medicine, SE-171 77 Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden. Department of Medical Biology, The Arctic University of Norway, NO-9037 Tromsø, Norway.
authors.forename: Aelita
authors.initials: A
authors.lastname: Konstantinell
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.
authors.forename: Riita
authors.initials: R
authors.lastname: Lahesmaa
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lentini
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: H Robert I
authors.initials: HR
authors.lastname: Liljenström
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Mattson
authors.affiliation: Futurum-Academy for Health and Care, County Council of Jönköping, SE-551 85 Jönköping, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Matussek
authors.affiliation: Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Mellergård
authors.affiliation: Laboratorio de Investigación en Enfermedades Infecciosas, LID, Universidad Peruana Cayetano Heredia, Lima PE-15102, Peru.
authors.forename: Melissa
authors.initials: M
authors.lastname: Mendez
authors.affiliation: Department of Clinical Neurosciences, Karolinska Institutet and Centrum for Molecular Medicine, SE-171 77 Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Cancer and Systems Biology Unit, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, ES-08908 Barcelona, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pujana
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.
authors.forename: Omid
authors.initials: O
authors.lastname: Rasool
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Cancer and Systems Biology Unit, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, ES-08908 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Serra-Musach
authors.affiliation: Futurum-Academy for Health and Care, County Council of Jönköping, SE-551 85 Jönköping, Sweden.
authors.forename: Margaretha
authors.initials: M
authors.lastname: Stenmarker
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.
authors.forename: Subhash
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.
authors.forename: Miro
authors.initials: M
authors.lastname: Viitala
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden. Department of Immunology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Colm E
authors.initials: CE
authors.lastname: Nestor
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden. mika.gustafsson@liu.se mikael.benson@liu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Benson
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics; D006255:Rhinitis, Allergic, Seasonal / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D059467:Transcriptome
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; D020598:Proto-Oncogene Proteins c-myb