Models of chromosome architecture and connection with the regulation of genetic expression

TL;DR

This paper explores models of chromosome folding and gene regulation using statistical physics, representing chromosomes as polymers interacting with DNA-binding proteins, and validates the models with experimental data and simulations.

Contribution

It introduces a physical model of chromosome architecture that explains experimental observations and links chromosome structure to gene regulation mechanisms.

Findings

Model explains transcription factory formation observed in vivo

Proposes a physical basis for DNA hairpin loop regulation by H-NS

Reproduces chromosome contact data from conformation capture experiments

Abstract

Increasing evidence suggests that chromosome folding and genetic expression are intimately connected. For example, the co-expression of a large number of genes can benefit from their spatial co-localization in the cellular space. Furthermore, functional structures can result from the particular folding of the chromosome. Such phenomena have in common to result from the binding of divalent proteins that can bridge regions sometimes far away on the DNA sequence. The physical system consisting of the chromosome interacting with divalent proteins can be very complex. As such, most of the mechanisms responsible for chromosome folding and for the formation of functional structures have remained elusive. Using methods from statistical physics, we investigated models of chromosome architecture. A common denominator of our approach has been to represent the chromosome as a polymer with bending rigidity and consider its interaction with a solution of DNA-binding proteins. Structures entailed by the binding of such proteins were then characterized at the thermodynamical equilibrium. Furthermore, we complemented theoretical results with Brownian dynamics simulations, allowing to reproduce more of the biological complexity. The main contributions of this thesis have been: (i) to provide a model for the existence of transcription factories characterized in vivo with fluorescence microscopy; (ii) to propose a physical basis for a conjectured regulatory mechanism of the transcription involving the formation of DNA hairpin loops by the H-NS protein as characterized with atomic-force microscopy experiments; (iii) to propose a physical model of the chromosome that reproduces contacts measured in chromosome conformation capture (CCC) experiments. Consequences on the regulation of transcription are discussed in each of these studies.