1. Kinetic proofreading model for nucleosome repositioning analysis
Guillaume Brysbaert, Marc Lensink, Raghvendra Pratap Singh, Rinaldo Zucca and Ralf Blossey
Institut de Recherche Interdisciplinaire, CNRS USR3078, 50 avenue de Halley, BP 70478, Villeneuve d'Ascq Cedex France
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Nucleosome
The crystal structure of the nucleosome core particle consisting of H2A , H2B , H3 and H4 core histones, and DNA. The view is from the top through the superhelical axis.
(en.wikipedia.org)
Nucleosomes, consisting each of 8 histones. Each histone has a tail that can be posttranslationaly modified. (Marks et al. 2001, Nature Reviews Cancer)
Some posttranslational modifications on histone tails: acetylations, methylations, phosphorylations, ubiquitinations (Bhaumik et al. 2007, Nature Structural & Molecular Biology)
Kinetic proofreading in chromatin remodeling
We have developed a kinetic proofreading model for nucleosome repositioning (Blossey R & Shiessel H 2008, HFSP Journal) . The model is based on the recognition of specific histone tail modifications by chromatin remodelers such as the bromodomain and the chromodomain. The coupling of highly energetic modifications to ATP-dependent motions of the nucleosomes constitutes a key element of a kinetic proofreading scheme, as originally postulated by Hopfield for protein translation (Hopfield JJ 1974, PNAS). A similar scenario was recently also invoked by Narlikar for the ISWI controlled repositioning of nucleosomes (Narlikar GJ 2010, Curr Opin Chem Biol).
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Specificity of recognition
SNF2 ATP-dependent chromatin remodelers are divided into 4 major families.
We have performed a data mining study of existing values of dissociation constants (Kd) of chromatin remodelers and modified histone tails. We normalized them with respect to the smallest and to the largest measured Kd value. The shapes of both bromodomains diagrams display the same behaviour with a strong preference towards more specific bindings (small Kd), compared to chromodomains diagrams shapes. Although these data are far from being conclusive, they could be indicative of a more specific, energetically-based recognition performed by bromodomains.
Bromodomains
Chromodomains
Clapier C & Cairns B 2009, Annu. Rev. Biochem
Genome wide analysis
The ultimate aim is to have a mechanistic understanding of histone tail modifications. Essential information to retrieve concerns how the different histone tail modifications are distributed along the genome, based on CHIP-SEQ data, then to correlate it with the specific recognition of the chromatin remodeling complexes, essentially via bromodomains and chromodomains. We want to study the relevance of the recognition energy for nucleosome repositioning.
Karlic et al 2010, PNAS