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Chromatin Remodeling Mechanisms – CHROME

Probe the structural dynamics of chromatin at the molecular level

Chromatin modulates how the genetic message contained in our DNA sequence is read. It involves the formation of many protein complexes and many levels of structural organization. Our aim is to analyse and understand the modifications of these structures that occur during the cell cycle and allow DNA to be read, copied and repaired

Analyse the genetic mechanisms and genetic errors linked to the constitution, the stability and the positioning of nucleosomes

DNA packaging within the cell nucleus, via the formation of nucleosomes and their organisation within chromatin, contributes to controlling gene expression in a subtle and complex manner. To understand these control mechanisms, and the pathologies which can result from faulty processes, it is necessary to construct molecular-scale models that will allow us to understand how changes within nucleosomes influence their behavior and their interactions with other cellular complexes. hopefully, such models will allow us to develop techniques to modify nucleosome function for either biological or therapeutic goals.

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

See «scientifc output«

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

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.

Project coordinator

Monsieur Richard LAVERY (Bioinformatique: Structures et Interactions, Bases Moléculaires et Structurales des Systèmes Infectieux) – richard.lavery@ibcp.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CNRS IAB UMR 5309
BISI Bioinformatique: Structures et Interactions, Bases Moléculaires et Structurales des Systèmes Infectieux
ENS-Lyon, CNRS Laboratoire de Biologie Moleculaire de la Cellule, ENS
INSERM U823 INSERM U823 - Institut Albert Bonniot

Help of the ANR 532,730 euros
Beginning and duration of the scientific project: December 2012 - 48 Months

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