Remodelers Organize Cellular Chromatin by Counteracting Intrinsic Histone-DNA Sequence Preferences in a Class-Specific Manner

Abstract

The nucleosome is the fundamental repeating unit of eukaryotic chromatin. Here, we assessed the interplay between DNA sequence and ATP-dependent chromatin-remodeling factors (remodelers) in the nucleosomal organization of a eukaryotic genome. We compared the genome-wide distribution of Drosophila NURD, (P)BAP, INO80, and ISWI, representing the four major remodeler families. Each remodeler has a unique set of genomic targets and generates distinct chromatin signatures. Remodeler loci have characteristic DNA sequence features, predicted to influence nucleosome formation. Strikingly, remodelers counteract DNA sequence-driven nucleosome distribution in two distinct ways. NURD, (P)BAP, and INO80 increase histone density at their target sequences, which intrinsically disfavor positioned nucleosome formation. In contrast, ISWI promotes open chromatin at sites that are propitious for precise nucleosome placement. Remodelers influence nucleosome organization genome-wide, reflecting their high genomic density and the propagation of nucleosome redistribution beyond remodeler binding sites. In transcriptionally silent early embryos, nucleosome organization correlates with intrinsic histone-DNA sequence preferences. Following differential expression of the genome, however, this relationship diminishes and eventually disappears. We conclude that the cellular nucleosome landscape is the result of the balance between DNA sequence-driven nucleosome placement and active nucleosome repositioning by remodelers and the transcription machinery.

Nucleosome Remodeling and Epigenetics

“…Interestingly, two related complexes, BAPand PBAP, share six subunits but differ in the signature subunits: Osa, dD4, and TTH for BAP; PB, BAP170, SAYP, and dBRD7 for PBAP (Fig. 8A) (Moshkin et al 2007;Moshkin et al 2012). The 'core complex" in the absence of these signature subunits is not functional in vivo.…”

The spring-loaded genome: Nucleosome redistributions are widespread, transient, and DNA-directed

“…An interesting observation arising from our study is that loci classified as DNA-directed have higher GC content; while loci classified as DNA-independent have lower GC content. It has been previously demonstrated that GC content confers different requirements for ATP-dependent chromatin remodelers (RamirezCarrozzi et al 2006(RamirezCarrozzi et al , 2009Moshkin et al 2012). SWI/SNF-independent genes have greater GC content around the TSS, whereas SWI/SNF-dependent genes have lower GC content.…”

“…This observation is consistent with multiple studies that have investigated a role for the ISWI family of chromatin remodelers. Genomic targets of ISWI family members have increased GC content (Moshkin et al 2012). Additionally, studies in yeast and flies have shown that in the absence of ISWI complexes, nucleosomes adopt DNA-encoded positions (Gkikopoulos et al 2011;Moshkin et al 2012).…”

“…Genomic targets of ISWI family members have increased GC content (Moshkin et al 2012). Additionally, studies in yeast and flies have shown that in the absence of ISWI complexes, nucleosomes adopt DNA-encoded positions (Gkikopoulos et al 2011;Moshkin et al 2012). It is interesting to speculate a role for ISWI at the DNA-directed loci in which this ATP-dependent remodeler ''pushes'' nucleosomes away from genetically encoded positions in the basal state (Moshkin et al 2012).…”

Regulation of ISWI chromatin remodelling activity

“…5a). The work of Moshkin et al (2012)) extended this concept, demonstrating that although ISWI target sites are predicted to be favourable for nucleosome formation because of an high GC content, ISWI remodellers tend to remove nucleosomes from the target loci, thus antagonizing in vivo and in vitro the DNA sequence driven nucleosome placement. ChIP-on-chip experiments suggested that dISWI preferentially binds nucleosome free regions located in close proximity to Transcriptional Start Site of genes, supporting the potential regulatory role played by the DNA sequence underlying the remodeller target site in the recruitment and the biological functions of dISWI (Sala et al 2011).…”