2 - The Role of Nucleosome Positioning in Genome Function and Evolution

Abstract

We use a physical model of nucleosome formation based on sequence-dependent DNA bending properties to investigate the role of nucleosome positioning in the multiscale coding of nuclear functions. We show the existence in most eukaryotic organisms of nucleosome-inhibitory energy barriers (NIEBs) that condition the statistical positioning of neighboring nucleosomes. In Saccharomyces cerevisiae, most of the nucleosome-depleted regions (NDRs) observed in vivo at transcription start sites (TSS) and active DNA replication origins indeed correspond to sequence-dependent excluding energy barriers up to finite-range remodeling action of external factors including transcription factors and ATP-dependent chromatin remodelers. If similar sequence-driven NDR regulation of transcription and replication initiation is likely to operate in different yeast species and probably in Caenorhabditis elegans, the situation is quite different in mammals where a high nucleosome affinity (high local GC content) is programmed at regulatory sequences to intrinsically restrict access to regulatory information that will mostly be used in vivo in an epigenetically controlled cell-type-dependent manner. In human, 1.6 millions of NIEBs and flanking nucleosome ordering are observed both in vitro and in vivo as covering ~37.5% of the genome. Likely encoded in the local GC content, these 1-kb-sized regions of intrinsic nucleosome occupancy are equally found in GC-rich and GC-poor isochores, in early and late replicating regions, in intergenic and genic regions but not at gene promoters and replication initiation loci. The comparison of interspecies and intraspecies rates of divergence confirms the existence of some selection pressure to maintain an optimal GC content depletion in NDRs relative to the local bulk GC content. We propose that these widely distributed chromatin patterns have been selected in human, and more generally in mammals and other higher eukaryotes, to impair the condensation of the nucleosomal array into the 30nm chromatin fiber, so as to facilitate the epigenetic regulation of nuclear functions in a multiscale cell-type-specific fashion.