The field of rheumatoid arthritis (RA) is moving into identification of patients as early as possible and the ultimate aim is to prevent RA becoming a chronic disease. To this end, we studied the... Show moreThe field of rheumatoid arthritis (RA) is moving into identification of patients as early as possible and the ultimate aim is to prevent RA becoming a chronic disease. To this end, we studied the phase of Clinically Suspect Arthralgia (CSA). Patients with arthralgia that were considered by the rheumatologist to have an increased risk to progress to RA (CSA) had indeed an increased risk of RA. In addition, subclinical MRI-inflammation preceded clinical arthritis with a few months. Future research will shed more light on processes underlying progression from CSA to RA and effectiveness of treatment initiation in the CSA phase. The severity of the course of RA is variable between patients and this cannot be yet accurately predicted. In this thesis, we performed studies that contributed to the understanding of these differences in severity. Three genetic risk factors for more severe joint damage progression (two non-HLA and one HLA variation) and one for arthritis persistence were identified. Further research on functional implications of the identified variants and whether they might be useful as biomarkers to guide treatment decisions is needed. Show less
Deelen, J.; Akker, E.B. van den; Trompet, S.; Heemst, D. van; Mooijaart, S.P.; Slagboom, P.E.; Beekman, M. 2016
A large part of the human genome consists of repetitive DNA. In this thesis two human diseases have been studied in which deregulation of repetitive DNA is a central feature: facioscapulohumeral... Show moreA large part of the human genome consists of repetitive DNA. In this thesis two human diseases have been studied in which deregulation of repetitive DNA is a central feature: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromere instability and facial anomalies (ICF) syndrome. FSHD is caused by the misexression of the transcription factor DUX4 in skeletal muscle. DUX4 is encoded in the D4Z4 repeat array and is silenced in healthy somatic tissues. In this thesis, several aspects of the epigenetic deregulation of DUX4 in FSHD are described. We have analysed possible correlations between disease severity and epigenetic organization of the D4Z4 repeat. Next we showed that cellular ageing results in deregulation of genomic regions like D4Z4. Moreover, we show that SMCHD1 is the main epigenetic repressor of DUX4 in somatic cells. We next showed that DUX4 misexpression results in the activation of an FSHD candidate gene, FRG2. Finally, we report the generation of a transgenic mouse model for FSHD. The disease mechanism of ICF syndrome remains to be elucidated. However, in this thesis we identify two new ICF disease genes. We highlight a role for all four known ICF genes in repressing repetitive DNA, suggesting functional convergence of these genes. Show less
Paneque, M.; Turchetti, D.; Jackson, L.; Lunt, P.; Houwink, E.; Skirton, H. 2016
Jasmonates (JAs) are crucial plant signaling molecules that regulate defense responses against wounding, insects and necrotrophic pathogens. The biosynthesis of JAs is regulated by a positive... Show moreJasmonates (JAs) are crucial plant signaling molecules that regulate defense responses against wounding, insects and necrotrophic pathogens. The biosynthesis of JAs is regulated by a positive feedback loop. This thesis reveals the transcriptional regulatory mechanism behind this positive feedback loop in Arabidopsis. The studies show that the bHLH-domain transcription factors MYC2, MYC3 and MYC4 positively regulate most JAs biosynthesis genes directly and by controlling the expression of ORA47 gene, encoding a regulator of JAs biosynthesis. Show less
Advances in technology have turned modern biology into a data-intensive enterprise. The advent of high-output technologies like Microarrays and Next-generation sequencing technologies has resulted... Show moreAdvances in technology have turned modern biology into a data-intensive enterprise. The advent of high-output technologies like Microarrays and Next-generation sequencing technologies has resulted in researchers grappling not just with huge volumes but also multiple types of data. While generation and storage of high-quality data are an important research focus, it is increasingly recognized that translating data into actionable information and insight is a critical research challenge. To infer reliable conclusions from the data, it is often necessary to integrate large amounts of heterogeneous data with different formats and semantics. Given the breadth and volume of data involved, this goal is best achieved through automated methods and tools for data integration and workflow management. This thesis presents automated strategies that combine bioinformatics and statistical methods to identify novel biomarkers in high-throughput OMICs datasets pertaining to the metabolic syndrome and to gain mechanistic insight into the underlying biological processes. An underlying theme in this thesis is data-driven approaches that generate plausible hypothesis which is followed by experimental verification. Show less
