Understanding the link between chromatin structure, chromosome conformation and gene regulation
[eng] Understanding the connection between DNA organization in the nucleus, and cell functioning is one of the most intriguing problems in biology. Although many interdisciplinary efforts have been developed for this aim, the mechanisms of DNA folding in such a large scale are largely unknown. There...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/150261 |
| Acceso en línea: | https://hdl.handle.net/2445/150261 http://hdl.handle.net/10803/668639 |
| Access Level: | acceso abierto |
| Palabra clave: | Regulació genètica Cromatina Cromosomes Genetic regulation Chromatine Chromosomes |
| Sumario: | [eng] Understanding the connection between DNA organization in the nucleus, and cell functioning is one of the most intriguing problems in biology. Although many interdisciplinary efforts have been developed for this aim, the mechanisms of DNA folding in such a large scale are largely unknown. Therefore, the complexity of genome structure requires different techniques to tackle several resolution levels. In this thesis, several scales of genome folding are studied using theoretical methods. First, we focus on the DNA sequence dependent properties which define the propensity of specific loci to be recognized by proteins, finding that the flexibility of specific DNA sequences might explain their prevalence in the genome. DNA sequence dependent properties are also important to define the first layer of chromatin organization: the nucleosome. Physical descriptors of the DNA sequence combined with the propensity for transcription factor binding are highly informative on the location of nucleosome depleted regions, which guide the position of +1 and –last nucleosomes, the rest of nucleosomes in the gene body being placed by statistical phasing. There is a clear correlation between transcriptional activity and nucleosome phasing at gene body, the causal relationship is transcription -> nucleosome organization rather than the opposite A package for the comparative analysis of nucleosome organization was also developed in this thesis to quantitative predict changes in nucleosome organization occurring when perturbations are introduced to the cell. Finally, we studied both the changes at the nucleosome level and at larger scale produced by the induction of DNA methylation on a natively unmethylated genome, developing a Hi-C based 3D model to gain insights into the chromatin rearrangements observed. We found very significant changes in chromatin structure induced by methylation, which are reflected in gene expression and cellular phenotype. Interestingly, these changes are found in a model organism that has not proteins prepared to recognize methylation, and accordingly can be assigned to intrinsic (not protein-mediated) effects of methylation. |
|---|