Modeling nucleosome mediated mechanisms of gene regulation

Abstract

The genomes of all eukaryotic organisms are packaged into nucleosomes, which are the fundamental units of chromatin, each composed of approximately 147 base pairs of DNA wrapped around a histone octamer. Because 70-90% of the eukaryotic genome is packaged into nucleosomes they modulate accessibility of DNA to transcription factors (TFs) and play an important role in regulation of transcription. This thesis is devoted to the mathematical modeling of effects which are caused by direct competition between nucleosomes and transcription factors. The contents of the thesis are organized as follows: in chapter 1 we introduce experimental methods and recent discoveries which have been made in chromatin biology. In chapter 2 we introduce a thermodynamic biophysical model for calculating nucleosome and transcription factor occupancies. We also introduce the statistical positioning effect and how it may affect the binding of transcription factors. In chapter 2 we mostly address a question of how competition with transcription factors can affect nucleosome positioning. We first examine nucleosome experimental data and address the question of reproducibility of the data across different experiments carried out in several labs. Then, we introduce a new method for the quality assessment of the prediction of the model and use it to optimize parameters of the model to fit experimental data. We focus on how transcription factors can explain observed in vivo nucleosome positioning and which transcription factors play crucial roles in establishing nucleosome patterns at the promoters of genes. In chapter 3 we address a question of how nucleosomes and promoter architecture affect binding of TFs. We model binding of TFs in the context of chromatin to a cluster of binding sites and investigate what features of the binding site cluster determine the main characteristics of TF binding. Finally, we study how TFBSs in real genomes are positioned relative to each other and show that there are certain biases in spacing between TFBSs, probably due to effects caused by competition with nucleosomes.