Numerous studies have contributed to our current understanding of autoimmune diseases (AIDs), however, pathogenesis of many AIDs can still not be fully explained. Both genetic factors and... Show moreNumerous studies have contributed to our current understanding of autoimmune diseases (AIDs), however, pathogenesis of many AIDs can still not be fully explained. Both genetic factors and environmental factors are involved in the onset of autoimmunity. Which mechanisms explain the contribution of these genetic and environmental factors to disease pathogenesis, and how the different factors interplay remain unanswered key questions. The studies presented in this thesis aimed at identifying and unravelling some of the enigmatic mechanisms in rheumatoid arthritis (RA) and systemic sclerosis (SSc). Show less
The transcription factor Sox2 controls the fate of pluripotent stem cells and neural stem cells. This gatekeeper function requires well-regulated Sox2 levels. We postulated that Sox2 regulation is... Show moreThe transcription factor Sox2 controls the fate of pluripotent stem cells and neural stem cells. This gatekeeper function requires well-regulated Sox2 levels. We postulated that Sox2 regulation is partially controlled by the Sox2 overlapping long non-coding RNA (lncRNA) gene Sox2ot. Here we show that the RNA levels of Sox2ot and Sox2 are inversely correlated during neural differentiation of mouse embryonic stem cells (ESCs). Through allele-specific enhanced transcription of Sox2ot in mouse Sox2eGFP knockin ESCs we demonstrate that increased Sox2ot transcriptional activity reduces Sox2 RNA levels in an allele-specific manner. Enhanced Sox2ot transcription, yielding lower Sox2 RNA levels, correlates with a decreased chromatin interaction of the upstream regulatory sequence of Sox2 and the ESC-specific Sox2 super enhancer. Our study indicates that, in addition to previously reported in trans mechanisms, Sox2ot can regulate Sox2 by an allele-specific mechanism, in particular during development. Show less
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and multiple organs of which the pathogenesis is poorly understood. Here we studied differentially expressed... Show moreSystemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and multiple organs of which the pathogenesis is poorly understood. Here we studied differentially expressed coding and non-coding genes in relation to SSc pathogenesis with a specific focus on antisense non-coding RNAs. Skin biopsy-derived RNAs from fourteen early SSc patients and six healthy individuals were sequenced with ion-torrent and analysed using DEseq2. Overall, 4901 genes with a fold change >1.5 and a false discovery rate < 5% were detected in patients versus controls. Upregulated genes clustered in immunological, cell adhesion and keratin-related processes. Interestingly, 676 deregulated non-coding genes were detected, 257 of which were classified as antisense genes. Sense genes expressed opposite of these antisense genes were also deregulated in 42% of the observed sense-antisense gene pairs. The majority of the antisense genes had a similar effect sizes in an independent North American dataset with three genes (CTBP1-AS2, OTUD6B-AS1 and AGAP2-AS1) exceeding the study-wide Bonferroni-corrected ρ-value (PBonf<0.0023, Pcombined = 1.1x10-9, 1.4x10-8, 1.7x10-6, respectively). In this study, we highlight that together with coding genes, (antisense) long non-coding RNAs are deregulated in skin tissue of SSc patients suggesting a novel class of genes involved in pathogenesis of SSc. Show less
Messemaker, T.C.; Frank-Bertoncelj, M.; Marques, R.B.; Adriaans, A.; Bakker, A.M.; Daha, N.; ... ; Kurreeman, F. 2016
