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Accueil > Research > Research teams > Computational Molecular Systems Biology > Projects

Computational Molecular Systems Biology

Mechanistic understanding of the histone code

Since 2008, the team has developed an interest in regulation of chromatin remodeling. Chromatin is thought to be controlled by a supposed “histone code” according to a hypothesis made by Strahl and Allis in 2000. The logic behind the enormous diversity of post-translational modifications on the histone tails, but also on the globular domains, remains still largely unexplained.We advocated the viewpoint that a subset of these modifications can be interpreted in their relation to mechanical processes acting on chromatin, i.e. at the positioning of nucleosomes along the DNA fiber. A dedicated molecular machinery exists for this purpose in the form of several different families of chromatin remodeling factors. These factors can both recognize post-translationally modified histone tails and act as molecular motors to displace nucleosomes.

For the regulation of the action of chromatin remodelers, an original idea had been proposed by Ralf Blossey and an external collaborator, Prof. Helmut Schiessel from Leiden University in the Netherlands, in 2008. They developed a so-called « kinetic proofreading » scenario, in which the recognition of specific histone marks is coupled to the ATP-dependent motor activity of chromatin remodelers. Via this nonequilibrium effect, well-known from other biological processes like mRNA translation, a means is provided for substrate selection for the remodeling factors. Our work therefore provided a first quantitative hint as to how a part of the supposed ‘histone code’ may be dynamically realized in eukaryote organisms, but at the time when it was proposed it lacked experimental confirmation.

In the course of our project, a similar scenario to ours was developed independently by Prof. Geeta Narlikar from the University of California/San Francisco (UCSF), for the particular case of ISWI remodelers which she had studied in single-molecule experiments. Prof. Narlikar’s work gave us the opportunity to continue the development of our models and in particular, with two post-docs (Florescu and Vandecan), to study the details of the dynamics of the process of chromatin remodeling by ISWI remodelers, both at the single molecule level and at the level of nucleosomal arrays. A number of publications have arisen from this work in the course of 2011-2015, both in collaboration with Prof. Schiessel as well as within the group (see Publication List).

The most recent activitivity in this field is our 2015 paper in which we discussed the regulation of the IFN-beta gene in the kinetic proofreading context, a topic on which much work remains to be done. In 2017, Ralf Blossey will publish a book on this topic with the title Chromatin : Structure, Dynamics, Regulation.