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The role of sequence, gene orientation, and intergenic distance in chromatin structure and function


Remarkable conservation of patterns of histone modifications and variants has been observed at active genes [1,2]. We show that genome-wide average distributions of chromatin marks relative to transcription start sites (TSSs) in early Drosophila melanogaster embryos are largely consistent with previously observed patterns in other organisms. This work describes qualitatively different chromatin domains and draws with functional inferences about these regional differences in modification patterns. We find `plateaus' of the histone variant, H2Av spanning transcriptionally inactive loci, as observed in mammalian cells [3]. These mixed cell populations from embryos exhibit distributions of chromatin marks similar to bivalent domains, specialized regions which extend across and beyong genes involved in developmental regulation and cell differentiation in mammalian stem cells; 5' ends of genes in these regions lack H2Av, regardless of the transcriptional state of the genes.

In spite of the agreement of our initial studies with similar work in other organisms or tissues, analysis of chromatin patterns for genes grouped with respect to promoter orientation and distance from the adjacent upstream gene identifies differences in the positions and enrichment levels of active mark peaks, as well as levels of gene activity. Analysis of published data from human CD4+ cells and Saccharomyces cerevisiae reveals that many of the relationships between promoter context and the distributions of active marks surrounding TSSs are conserved among widely divergent eukaryotes. We propose that short-range, distance-dependent synergistic interactions between neighboring promoters impact both chromatin state and gene activity.

The functional consequences of DNA sequence variation for the specificity and stability of nucleosome associations are largely unknown but open to new avenues of investigation based on emerging DNA sequencing technologies. We present preliminary results on interaction between molecular evolution and nucleosome positioning in Drosophila. Base composition surrounding nucleosomes isolated from melanogaster embryos supports some level sequence-encoded higher order structure with a periodicity of ~200bp. Analysis of the interspecific divergence shows that the rates of change in these regions support an equilibrium model maintaining these patterns. We note a substantially accelerated GC->AT rate on the melanogaster lineage. Dinucleotide periodicities across nucleosomal fragments are quite similar between melanogaster and simulans, and we find good support for conserved positional changes in in simulans relative to nucleosomes isolated from melanogaster.

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