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dc.contributor.authorFernandes, Sunjay Jude
dc.contributor.authorMorikawa, Hiromasa
dc.contributor.authorEwing, Ewoud
dc.contributor.authorRuhrmann, Sabrina
dc.contributor.authorJoshi, Rubin Narayan
dc.contributor.authorLagani, Vincenzo
dc.contributor.authorKarathanasis, Nestoras
dc.contributor.authorKhademi, Mohsen
dc.contributor.authorPlanell, Nuria
dc.contributor.authorSchmidt, Angelika
dc.contributor.authorTsamardinos, Ioannis
dc.contributor.authorOlsson, Tomas
dc.contributor.authorPiehl, Fredrik
dc.contributor.authorKockum, Ingrid
dc.contributor.authorJagodic, Maja
dc.contributor.authorTegner, Jesper
dc.contributor.authorGomez-Cabrero, David
dc.date.accessioned2019-08-25T08:58:37Z
dc.date.available2019-08-25T08:58:37Z
dc.date.issued2019-08-19
dc.identifier.citationFernandes, S. J., Morikawa, H., Ewing, E., Ruhrmann, S., Joshi, R. N., Lagani, V., … Gomez-Cabrero, D. (2019). Non-parametric combination analysis of multiple data types enables detection of novel regulatory mechanisms in T cells of multiple sclerosis patients. Scientific Reports, 9(1). doi:10.1038/s41598-019-48493-7
dc.identifier.doi10.1038/s41598-019-48493-7
dc.identifier.urihttp://hdl.handle.net/10754/656595
dc.description.abstractMultiple Sclerosis (MS) is an autoimmune disease of the central nervous system with prominent neurodegenerative components. The triggering and progression of MS is associated with transcriptional and epigenetic alterations in several tissues, including peripheral blood. The combined influence of transcriptional and epigenetic changes associated with MS has not been assessed in the same individuals. Here we generated paired transcriptomic (RNA-seq) and DNA methylation (Illumina 450 K array) profiles of CD4+ and CD8+ T cells (CD4, CD8), using clinically accessible blood from healthy donors and MS patients in the initial relapsing-remitting and subsequent secondary-progressive stage. By integrating the output of a differential expression test with a permutation-based non-parametric combination methodology, we identified 149 differentially expressed (DE) genes in both CD4 and CD8 cells collected from MS patients. Moreover, by leveraging the methylation-dependent regulation of gene expression, we identified the gene SH3YL1, which displayed significant correlated expression and methylation changes in MS patients. Importantly, silencing of SH3YL1 in primary human CD4 cells demonstrated its influence on T cell activation. Collectively, our strategy based on paired sampling of several cell-types provides a novel approach to increase sensitivity for identifying shared mechanisms altered in CD4 and CD8 cells of relevance in MS in small sized clinical materials.
dc.description.sponsorshipWe thank all the patients who have been willing to contribute their blood samples to make this study possible. We acknowledge Peri Noori from the Unit of Computational Medicine for laboratory management. This work was supported by grants from the Swedish Research Council, the Swedish Brain Foundation, the Stockholm County Council (ALF project) and AstraZeneca (AstraZeneca-Science for Life Laboratory collaboration). J.T was supported by funds from King Abdullah University for Science and Technology. IK was supported by Horizon 2020 MultipleMS grant no 733161. VL, NK, and IT were supported by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n. 617393 and STATegra EU FP7 project, No 306000.
dc.publisherSpringer Nature
dc.relation.urlhttp://www.nature.com/articles/s41598-019-48493-7
dc.rightshis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0
dc.titleNon-parametric combination analysis of multiple data types enables detection of novel regulatory mechanisms in T cells of multiple sclerosis patients.
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.identifier.journalScientific reports
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionUnit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
dc.contributor.institutionScience for Life Laboratory, Solna, Stockholm, Sweden
dc.contributor.institutionDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
dc.contributor.institutionInstitute of Chemical Biology, Ilia State University, Tbilisi, Georgia.
dc.contributor.institutionGnosis Data Analysis PC, Heraklion, Greece.
dc.contributor.institutionComputer Science Department, University of Crete, Heraklion, Crete, Greece.
dc.contributor.institutionComputational Medicine Center, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA, 19107, USA
dc.contributor.institutionTranslational Bioinformatics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.
dc.contributor.institutionTranslational Bioinformatics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
dc.contributor.institutionInstitute for Immunology, Biomedical Center, Ludwig-Maximilians-Universität, München, 82152, Planegg-Martinsried, Germany
dc.contributor.institutionMucosal and Salivary Biology Division, King’s College London Dental Institute, London, SE1 9RT, United Kingdom
kaust.personMorikawa, Hiromasa
kaust.personTegner, Jesper
refterms.dateFOA2019-08-25T08:59:52Z
dc.date.published-online2019-08-19
dc.date.published-print2019-12


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his article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as his article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.