Looping and Long-Distance Communication on Chromatin

Abstract

Although the genetic messages in DNA are stored in a linear sequence of base pairs, the genomes of living species are highly packed and organized three-dimensional systems. Gene expression is regulated by DNA sites that often lie far apart along the genomic sequence and hence depends on cooperation between tight packing and protein-induced deformations of DNA. For example, eukaryotic histones, which wrap and package DNA into chromatin, are known to facilitate the communication between distant transcription factors by promoting the formation of chromatin loops. In order to clarify the role of histones and DNA deformation in chromatin looping, we have developed a structurally-based model of chromatin at the resolution of a single base pair and performed Monte-Carlo simulations. Our model successfully reproduces experimental measurements of gene expression induced by proteins bound to distant genomic sites on DNA fragments decorated by arrays of nucleosomes. We found in our simulations that changes, of the order of a few base pairs, in the spacing between nucleosomes give rise to a great diversity of fiber structures and looping probabilities. We are using our model to investigate the role of histone tails on nucleosome-nucleosome interactions and chromatin looping. We also study the interplay between local chromatin architecture and chromatin loop formation by simulating fibers with nucleosome-depleted regions and different spacing between the nucleosomes. In addition, we are able to model the presence of the protein assemblies used in the experiments to induce gene expression (RNA polymerase and NtrC) and to characterize their influence on chromatin structure and looping. The combination of simulations and experiments gives us the ability to relate local changes in nucleosome composition and chromatin architecture to the looping propensities of fluctuating chromatin fibers.