Marenduzzo, Davide

Brackley, Chris

Wiese, Oliver Simon

2020-05-18T11:48:10Z

2020-05-18T11:48:10Z

2020-06-25

In this thesis, I present the results from my research into the properties and organisation of chromatin structures at a nucleosome resolution. Nucleosomes, a secondary structure of DNA, are essential to the compaction and protection of DNA. However, they also play a role in the regulation of the expression of genes through changes in the 3D conformation of the chromatin fibre. The initial work, described in chapter 3, was carried out by looking at the three dimensional conformation of the chromatin structure in Saccharomyces cerevisiae (brewers yeast). Data from a recently developed technique called “Micro-C” (published by Hsieh et. al. [1]) is used to build a contact map, detailing the interactions between nucleosomes in 3D. This raw contact data is translated to a nucleosome resolution by pairing it with nucleosome occupancy data (published by Dang et. al.[2]) to produce a nucleosome resolution contact map. A finding of the Micro-C experiments were small chromosomally interacting domains not previously observed in yeast. These “micro-domains” are at a much smaller length scale than previously observed domains in eukaryotes, typically only containing a few yeast genes per micro-domain. The nucleosome occupancy data used to generate the nucleosome resolution maps can also be used to feed a simple “beads-on-a-string” computer simulation model discussed in chapter 4. The simulation model can be used to generate chromatin conformations. The output from the simulations can then be compared to the experimental data allowing us to deduce that just the spacing of the nucleosomes along the DNA has a significant effect on the position of domains in yeast chromosomes. The simulation output can also replicate domain boundaries to a high degree of accuracy compared when to the experimental data. Surprisingly a more detailed model does not improve the performance of feature replication. One of the primary factors driving the formation of these micro-domains seems to be the highly irregular nucleosome spacing found in yeast seldom discussed in the literature. When compared to the average nucleosome spacing in yeast, micro-domain boundaries have a significantly larger spacing. Finally, in chapter 5 the findings from yeast were then taken and the same model was applied to data for the human genome in order to make predictions about the chromatin structure. The preliminary and speculative results suggest that micro-domains are also found in humans at a sub gene level and boundaries of these micro-domains are again preferentially found at long linkers.

https://hdl.handle.net/1842/37061

http://dx.doi.org/10.7488/era/362

en

The University of Edinburgh

O. Wiese, D. Marenduzzo, and C. A. Brackley, “Nucleosome positions alone can be used to predict domains in yeast chromosomes,” Proceedings of the National Academy of Sciences, 2019

Saccharomyces cerevisiae

chromatin

computational models

micro-domain boundaries

nucleosome spacing

nucleosome interaction model

chromatin fibre model

Computer simulations of chromatin structures at nucleosome resolution

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy