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

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dc.contributor.author Gustafsson, Mika
dc.contributor.author Gawel, Danuta R.
dc.contributor.author Alfredsson, Lars
dc.contributor.author Baranzini, Sergio
dc.contributor.author Bjorkander, Janne
dc.contributor.author Blomgran, Robert
dc.contributor.author Hellberg, Sandra
dc.contributor.author Eklund, Daniel
dc.contributor.author Ernerudh, Jan
dc.contributor.author Kockum, Ingrid
dc.contributor.author Konstantinell, Aelita
dc.contributor.author Lahesmaa, Riita
dc.contributor.author Lentini, Antonio
dc.contributor.author Liljenstrom, H. Robert I.
dc.contributor.author Mattson, Lina
dc.contributor.author Matussek, Andreas
dc.contributor.author Mellergard, Johan
dc.contributor.author Mendez, Melissa
dc.contributor.author Olsson, Tomas
dc.contributor.author Pujana, Miguel A.
dc.contributor.author Rasool, Omid
dc.contributor.author Serra-Musach, Jordi
dc.contributor.author Stenmarker, Margaretha
dc.contributor.author Tripathi, Subhash
dc.contributor.author Viitala, Miro
dc.contributor.author Wang, Hui
dc.contributor.author Zhang, Huan
dc.contributor.author Nestor, Colm E.
dc.contributor.author Benson, Mikael
dc.date.accessioned 2019-02-06T14:53:40Z
dc.date.available 2019-02-06T14:53:40Z
dc.date.issued 2015
dc.identifier.uri https://hdl.handle.net/20.500.12866/5446
dc.description.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. en_US
dc.language.iso eng
dc.publisher American Association for the Advancement of Science
dc.relation.ispartofseries Science Translational Medicine
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Humans en_US
dc.subject Genome-Wide Association Study en_US
dc.subject Transcriptome en_US
dc.subject Polymorphism, Single Nucleotide en_US
dc.subject Gene Regulatory Networks en_US
dc.subject CD4-Positive T-Lymphocytes/immunology/metabolism en_US
dc.subject GATA3 Transcription Factor/genetics en_US
dc.subject Multiple Sclerosis/diagnosis/genetics/immunology en_US
dc.subject Proto-Oncogene Proteins c-maf/genetics en_US
dc.subject Proto-Oncogene Proteins c-myb/genetics en_US
dc.subject Rhinitis, Allergic, Seasonal/diagnosis/genetics/immunology en_US
dc.title A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1126/scitranslmed.aad2722
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.00
dc.relation.issn 1946-6242


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