Influence of the genomic sequence on the primary structure of chromatin

Abstract

As an important actor in the regulation of nuclear functions, the nucleosomal organization of the 10 nm chromatin fiber is the subject of increasing interest. Recent high-resolution mapping of nucleosomes along various genomes ranging from yeast to human, have revealed a patchy nucleosome landscape with alternation of depleted, well positioned and fuzzy regions. For many years, the mechanisms that control nucleosome occupancy along eukaryotic chromosomes and their coupling to transcription and replication processes have been under intense experimental and theoretical investigation. A recurrent question is to what extent the genomic sequence dictates and/or constrains nucleosome positioning and dynamics? In that context we have recently developed a simple thermodynamical model that accounts for both sequence specificity of the histone octamer and for nucleosome–nucleosome interactions. As a main issue, our modelling mimics remarkably well in vitro data showing that the sequence signaling that prevails are high energy barriers that locally inhibit nucleosome formation and condition the collective positioning of neighboring nucleosomes according to thermal equilibrium statistical ordering. When comparing to in vivo data, our physical modelling performs as well as models based on statistical learning suggesting that in vivo bulk chromatin is to a large extent controlled by the underlying genomic sequence although it is also subject to finite-range remodelling action of external factors including transcription factors and ATP-dependent chromatin remodellers. On the highly studied S. cerevisiae organism, we discuss the implications of the highlighted ‘positioning via excluding’ mechanism on the structure and function of yeast genes. The generalization of our physical modelling to human is likely to provide new insight on the isochore structure of mammalian genomes in relation with their primary nucleosomal structure.

Keywords:

• chromatin
• nucleosome
• DNA sequence
• physical model
• statistical ordering

Acknowledgements

We are very grateful to Y. d'Aubenton-Carafa, B. Audit, M. Barbi, C. Lavelle, R. Lavery, V. Miele, C. Thermes, A. Travers and J.M. Victor for very stimulating and fruitful discussions. This research was supported by the Conseil Régional Rhône-Alpes (project ‘Le rôle de la séquence sur la structure et la dynamique de la chromatine’, Emergence 2005) and the Agence Nationale de la Recherche ‘Programme Physique et Chimie du Vivant’ (project ‘DNAnucl: Influence de la séquence ADN sur la structure et la dynamique du nucléosome’, PCV2006).