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DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus (SLE)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-310387OAI: oai:DiVA.org:uu-310387DiVA: diva2:1056480
Available from: 2016-12-14 Created: 2016-12-14 Last updated: 2016-12-14
In thesis
1. Epigenetic and Gene Expression Signatures in Systemic Inflammatory Autoimmune Diseases
Open this publication in new window or tab >>Epigenetic and Gene Expression Signatures in Systemic Inflammatory Autoimmune Diseases
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Autoimmune diseases are clinical manifestations of a loss-of-tolerance of the immune system against the body’s own substances and healthy tissues. Primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE) are two chronic inflammatory autoimmune diseases characterized by autoantibody production and an activated type I interferon system. Although the precise mechanisms leading to autoimmune processes are not well defined, recent studies suggest that aberrant DNA methylation and gene expression patterns may play a central role in the pathogenesis of these disorders. The aim of this thesis was to investigate DNA methylation and gene expression in pSS and SLE on a genome-wide scale to advance our understanding of how these factors contribute to the diseases and to identify potential biomarkers and novel treatment targets.

In study I, differential DNA methylation was analyzed in multiple tissues from pSS patients and healthy controls. We identified thousands of CpG sites with perturbed methylation; the most prominent finding was a profound hypomethylation at regulatory regions of type I interferon induced genes in pSS. In study II, a cases-case study comparing DNA methylation in pSS patients with high fatigue to patients with low fatigue, we found methylation patterns associated to the degree of fatigue. In study III, RNA-sequencing was applied to investigate the transcriptome of B cells in pSS in comparison to controls. Increased expression of type I and type II interferon regulated genes in pSS was observed, indicating ongoing immune activation in B cells. In study IV, the impact of DNA methylation on disease susceptibility and phenotypic variability in SLE was investigated. We identified DNA methylation patterns associated to disease susceptibility, SLE manifestations and different treatments. In addition, we mapped methylation quantitative trait loci and observed evidence for genetic regulation of DNA methylation in SLE.  

In conclusion, the results presented in this thesis provide new insights into the molecular mechanisms underlying autoimmunity in pSS and SLE. The studies confirm the central role of the interferon system in pSS and SLE and further suggest novel genes and mechanisms to be involved in the pathogenesis these autoimmune diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1286
Keyword
Autoimmunity, DNA methylation, Primary Sjögren’s syndrome, Systemic lupus erythematosus, Gene expression, Type I interferon system, Epigenetics
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-310388 (URN)978-91-554-9782-8 (ISBN)
Public defence
2017-02-17, Enghoffsalen, entrance 50, ground floor, Uppsala University Hospital, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2017-01-26 Created: 2016-12-14 Last updated: 2017-02-01

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