Chromatin Remodeling Mechanisms – CHROME

The CHROME project will use the tools of molecular biology, biochemistry, biophysics and molecular modelling to analyse modifications in the structure, stability and positioning of nucleosomes. This involves novel experimental techniques that can probe and visualise individual nucleosomes and the development of new modelling approaches that can deal with very large molecular complexes

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Understand the impact of changes in the constitution of nucleosomes and predict their biological consequences through the development of models incorporating all the experimental and biophysical data obtained during the project

We show that phosphorylation of the N-terminal of the centromeric protein CENP-A (a variant of the nucleosomal histone H3) is necessary for recruiting the protein CENP-E (possibly via another bridging protein 14-3-3). This constitutes a vital step in the complex process of cell division.

D. Goutte-Gattat, M. Shuaib, K. Ouararhni, T. Gautier, D.A. Skoufias, A. Hamiche, S. Dimitrov (2013) PNAS 110, 8579-8584.

This project aims at understanding how chromatin-remodeling machines work by using a combination of innovative experimental and theoretical approaches and building on the recent discovery of an unexpected remodeling intermediate. Chromatin remodeling is a vital process within eukaryotic cells. It is involved in controlling gene expression, in epigenetic phenomena, and also in several human pathologies. Despite many years of study, how multicomponent remodeling machines work remains unknown. A breakthrough made by the experimental teams involved in this project has shown that remodeling need not be a continuous process, as previously supposed. The RSC chromatin remodeler in fact functions via a two-step mechanism, forming, releasing, and then rebinding and mobilizing a stable intermediate (a "remosome") containing 35-40 bp more DNA than canonical nucleosomes. In combination with a team specialized in modeling biomacromolecules and their complexes, this project will characterize remosome structure and stability, determine how a two-step process conditions the overall remodeling mechanism, test its generality, and its sensitivity to compositional and environmental factors. This project relies on bringing together biophysical, biochemical, biological and modeling data. The recognized expertise of the contributing teams, carefully designed structural and functional probe experiments, and a constant feedback between experiment and theory will provide the means to decode a complex and vital process with a significant impact on fundamental biology and important implications for human health.