Determinants of nucleosome organisation and transcription regulation by histone marks

Thesis

Epigenetics is the study of heritable changes in gene expression that do not involve changes in the underlying DNA sequence. Epigenetic pathways appeared in eukaryotes where multicellular organisms differentiate into different cell types, associated with different phenotypes. The differentiation process is achieved by modifications of the chromatin structure which, by altering the access of trans-factors to the DNA, result in gene activation and repression. Epigenetic mechanisms are therefore viewed as an "extra" layer of information that modulate the genetic information in time and space, necessary for the development and the response to environment stimuli. Although the recent development of high-throughput sequencing technologies has provided an unprecedented insight into epigenetic pathways, the mechanisms controlling the chromatin dynamic as well as their downstream effects on cellular processes are far from being fully understood.

In this thesis, our focus will be restricted to mechanisms acting on the nucleosome level. The first chapter will present the factors known to influence nucleosome positioning as well as the challenges related to the measurement of the nucleosome architecture. The second chapter will introduce a statistical approach, NucleoFinder, capable of identifying nucleosomes consistently positioned in a population of cells. In chapter three, we will make use of NucleoFinder to investigate the importance of cis and trans-factors on the nucleosome architecture in human and show that, despite variation across functional regions, cis-factors have a very modest in influence on nucleosome positioning. Finally, in chapter four, we will aim to identify clusters of histone modifications specific to functionally distinct regions, characterize their function and their association with gene expression level.

Authors: Becker, JFC

• Publication date: 2012
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: epigenetics; gene regulation; nucleosome position
• Subjects: Bioinformatics (life sciences); Pattern recognition (statistics)