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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Functional characterisation of rheumatoid arthritis risk loci

Mcgovern, Amanda Jane January 2016 (has links)
Rheumatoid arthritis (RA) is a complex autoimmune disease affecting approximately 1% of the population. Multiple factors contribute to the development of RA, with genetic factors accounting for around 60% of the disease risk. Over the last few years, genome-wide association studies (GWAS) have successfully been used to identify regions of the genome predisposing to complex disease. There are now 101 confirmed RA risk loci, but for the vast majority of these loci the causal gene and causal variant remain unidentified and therefore, their function in disease is unexplored. The majority of genetic variants, or single nucleotide polymorphisms (SNPs), associated with disease map to non-coding enhancer regions, which may regulate transcription through long-range interactions with their target genes. The aims of this project were to identify the causal genes within an RA locus, pinpoint the causal variants and elucidate the mechanisms by which the variants modify gene function. Capture Hi-C (CHi-C) was carried out with the aim of identifying long range interactions between disease-associated SNPs and genes in four related autoimmune diseases. Many long-range interactions were identified which implicated novel candidate genes, interactions involving multiple genetic loci which had a common target, and interactions with loci which had previously been implicated in disease. Complex interaction patterns were observed in many of the disease associated loci, particularly in the 6q23 locus which is associated with a number of autoimmune diseases and is the focus of the present thesis. Within the 6q23 locus, associated SNPs lie a large distance from any gene (>180kb) making it difficult to pinpoint the exact causal gene. Results from CHi-C and chromosome conformation capture (3C-qPCR) experiments indicated that restriction fragments containing disease associated intergenic SNPs could display genotype-specific interactions with genes associated with autoimmunity (IL20RA and IFNGR1). Interactions could also be detected with long non-coding RNAs (lncRNAs), The lead SNP in the 6q23 region is in tight LD with eight other SNPs which are equally likely to be causal. Bioinformatics analysis suggested that the most plausible causal SNP in the 6q23 intergenic region was rs6927172, as it maps to an enhancer in both B-cells and T-cells, is in a DNaseI hypersensitivity cluster, shows transcription factor binding and is in a conserved region. Chromatin immunoprecipitation (ChIP) demonstrated binding of chromatin marks of active enhancers (H3K4me1 and H3K27ac) and the transcription factors BCL3 and NF-κB to the rs6927172 SNP target site in Jurkat T-cells and GM12878 B-cells, suggesting the risk allele could be associated with increased regulatory activity. In conclusion, these results show that CHi-C can help identify novel GWAS causal genes with the potential to suggest novel therapeutic targets. For example IL20RA is already a target for a monoclonal antibody which has been shown to be effective in treating RA in clinical trials. This project has also provided compelling evidence that the autoimmune risk variant in the 6q23 locus, rs6927172, is within a complex gene regulatory region, involving multiple immune genes and regulatory elements, such as lncRNAs.
2

Systematic comparison of gene regulatory datasets using experimentally validated enhancers

Dong, Xue January 2020 (has links)
Promoter-enhancer interactions are essential for gene regulating, Capture Hi-C is a chromosome conformation capture method to map promoter-enhancer interactions at high resolution. We have Capture Hi-C data forGM12878 cells, immortalized primary B lymphocytes, in three replicates. Although Capture Hi-C maps enhancer elements together with the promoters they regulate, the overlap between enhancer datasets produced by other methods such as ChIP-seq and Capture Hi-C is lower than expected. In order to understand the reasons for lower overlap, we investigated the enhancer potential of replicated and non-replicated Capture Hi-C interactors, as well as enhancer overlapping and non-overlapping Capture Hi-C interactors. We performed a systematic comparison between our interactor and experimental regulatory and transcriptomic datasets to determine the extent of enhancer mapping. The results show replicated interactors have higher enhancer potential than non-replicated ones. However, there is evidence that interactors not overlapping with experimental validated regulatory datasets can also potentially be true enhancers.
3

Functional reorganization of the yeast genome during the cell cycle / Réorganisation fonctionnelle du génome de la levure durant le cycle cellulaire

Lazar-Stefanita, Luciana 26 September 2017 (has links)
Des décennies d'études ont montré que la structure de la chromatine est étroitement liée aux processus métaboliques de l'ADN. Une bonne organisation des chromosomes tout au long du cycle cellulaire est particulièrement importante pour assurer le maintien de l'intégrité de l'ADN. Le but de mon projet de doctorat était de caractériser dans quelle mesure la réorganisation de la chromatine pendant le cycle cellulaire pourrait influencer la stabilité des chromosomes. Pour ce faire, nous avons d'abord effectué une étude complète de la réorganisation des chromosomes de la levure modèle Saccharomyces cerevisiae pendant tout un cycle cellulaire. Ce travail, en plus de récapituler les caractéristiques chromosomiques attendues, a conduit à la caractérisation de structures chromosomiques particulières, telle qu'une boucle d'ADN reliant l'ADNr et les centromères. Le rôle des complexes SMC et des microtubules a été étudié en profondeur. Une deuxième partie de mon travail a porté sur la description de l'organisation de la chromatine de cellules qui ont quitté le cycle cellulaire prolifératif et sont entrées en quiescence. Nous avons ainsi caractérisé le statut dense de l'hétérochromatine silencieuse dans des loci spécifiques tels que les télomères. Enfin, nous avons essayé de mieux comprendre l'interaction fonctionnelle entre la stabilité chromosomique et l'architecture 3D du génome durant la réplication en étudiant la stabilité génomique à des sites de pause de réplication. Nos résultats indiquent une adaptabilité frappante des structures de réplication sous différentes contraintes. Le travail futur vise à cartographier les réarrangements chromosomiques dépendants de la réplication. / Decades of studies showed that chromatin structure is tightly linked to DNA related metabolic processes, through the dynamic regulation of a myriad of molecular factors. The proper organization of chromosomes is notably important to ensure the maintenance of DNA integrity during cell cycle progression. Using the model S. cerevisiae, the aim of my PhD project was to characterize to which extent chromatin reorganization during the cell cycle may influence chromosome stability. To do so, we first generated a comprehensive genome-wide study of the reorganization of yeast’s chromosomes during an entire cell cycle. This work, besides recapitulating expected chromosomal features of the replication and mitotic stages, led to the characterization of peculiar chromosome structures such as a DNA loop bridging the rDNA and the centromeres. The role of structural maintenance of chromosomes (SMC) complexes and of microtubules were thoroughly investigated. A second part of my work focused on describing features of the chromatin organization of cells that exited the proliferative cell cycle and entered into quiescence. We characterized the dense status of silenced heterochromatin at specific loci, such as telomeres, in relation to the silent information regulators (SIRs). Finally, we tried to achieve a better understanding of the functional interplay between chromosome stability and the 3D genome architecture during replication, by investigating the genomic stability at replication pausing sites. Overall, our results point at a striking plasticity of replication structures to different stresses. Future work aims to map replication-dependent chromosomal rearrangements on the genomic maps.

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