Influence of the genomic sequence on the primary structure of chromatin

Abstract

International audienceAs 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

Epigenetic regulation of the human genome: coherence between promoter activity and large-scale chromatin environment

“…If specific chromatin configurations may be dictated by the DNA sequence itself (Satchwell et al 1986;Ioshikhes et al 1996;Widom 2001;Segal et al 2006;St-Jean et al 2008;Milani et al 2009;Arneodo et al 2011;Chevereau et al 2011;Travers et al 2012;Struhl & Segal 2013), the chromatin structure is subject to various epigenetic modifications in any given cell type, including DNA methylation, histone modifications, histone variant incorporation and DNA-binding proteins (Kouzarides 2007;Zhou et al 2011;Zentner & Henikoff 2013). Recent technical advances in genomics and epigenomics including the combination of chromatin immunoprecipitation (ChIP) with massive parallel sequencing (ChIP-Seq) ) have made available a wealth of genome-wide data in various eukaryotic organisms, from budding yeast, to plants, worm, fly and mammals (Bernstein et al 2007; The ENCODE Project Consortium 2007; Rando & Chang 2009;Roudier et al 2009;Gerstein et al 2010;Kharchenko et al 2010; The modENCODE Consortium 2010; Feng & Jacobsen 2011;The ENCODE Project Consortium 2011).…”

Large replication skew domains delimit GC-poor gene deserts in human

“…To some extent, these NFRs were shown to be encoded in the DNA sequence via high energy barriers that (i) impair nucleosome formation and (ii) condition the collective nucleosomal organization observed over rather large distances along the chromatin fiber Vaillant et al, 2007Vaillant et al, , 2010Chevereau et al, 2009Chevereau et al, , 2011Milani et al, 2009;Mavrich et al, 2008;Miele et al, 2008;Segal and Widom, 2009;Radman-Livaja and Rando, 2010). Since the GC content in the -U domains is 40% (Fig.…”

“…Since the GC content in the -U domains is 40% (Fig. 3B) which is comparable to the GC content ∼39% homogeneously observed along S. cerevisiae chromosomes, we used here the same physical modeling of nucleosome formation energy based on sequence-dependent DNA bending properties originally introduced to model nucleosome occupancy in yeast (Vaillant et al, , 2010Chevereau et al, 2009Chevereau et al, , 2011Milani et al, 2009) (Section 2). We first validated this model by showing that in vivo genome-wide nucleosome occupancy data in human (Schones et al, 2008) display nucleosome depleted regions that strongly correlated with the predicted NFR positions along human light isochores .…”

“…The coordinates of the NFRs predicted by the physical model defined in (Vaillant et al, , 2010Chevereau et al, 2009;Milani et al, 2009) were obtained from the authors (Chevereau et al, 2011). This theoretical model amounts to compute the energy required for nucleosome formation based on sequence-dependent bending properties Chevereau et al, 2011).…”

“…This theoretical model amounts to compute the energy required for nucleosome formation based on sequence-dependent bending properties Chevereau et al, 2011).…”