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Sci Transl Med. 2015 Nov 11;7(313):313ra178. doi: 10.1126/scitranslmed.aad2722.

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

Author information

1
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.
2
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, SE-581 83 Linköping, Sweden.
3
Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Solna, Sweden.
4
Department of Neurology, University of California, San Francisco, CA 94158, USA.
5
Futurum-Academy for Health and Care, County Council of Jönköping, SE-551 85 Jönköping, Sweden.
6
Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine, Linköping University, SE-581 83 Linköping, Sweden.
7
Department of Clinical and Experimental Medicine, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, SE-581 83 Linköping, Sweden.
8
Department of Clinical Immunology and Transfusion Medicine, Linköping University, SE-581 83 Linköping, Sweden.
9
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.
10
Department of Clinical Neurosciences, Karolinska Institutet and Centrum for Molecular Medicine, SE-171 77 Stockholm, Sweden.
11
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.
12
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.
13
Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, SE-581 83 Linköping, Sweden.
14
Laboratorio de Investigación en Enfermedades Infecciosas, LID, Universidad Peruana Cayetano Heredia, Lima PE-15102, Peru.
15
Program Against Cancer Therapeutic Resistance (ProCURE), Cancer and Systems Biology Unit, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, ES-08908 Barcelona, Spain.
16
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.
17
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.

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.

PMID:
26560356
DOI:
10.1126/scitranslmed.aad2722
[Indexed for MEDLINE]
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