Abstract
Near promoters, both nucleosomes and CpG sites form characteristic spatial patterns. Previously, nucleosome depleted regions were observed upstream of transcription start sites and nucleosome occupancy was reported to correlate both with CpG density and the level of CpG methylation. Several studies imply a causal link where CpG methylation might induce nucleosome formation, whereas others argue the opposite, i.e., that nucleosome occupancy might influence CpG methylation. Correlations are indeed evident between nucleosomes, CpG density and CpG methylation—at least near promoter sites. It is however less established whether there is an immediate causal relation between nucleosome occupancy and the presence of CpG sites—or if nucleosome occupancy could be influenced by other factors. In this work, we test for such causality in human genomes by analyzing the three quantities both near and away from promoter sites. For data from the human genome we compare promoter regions with given CpG densities with genomic regions without promoters but of similar CpG densities. We find the observed correlation between nucleosome occupancy and CpG density, respectively CpG methylation, to be specific to promoter regions. In other regions along the genome nucleosome occupancy is statistically independent of the positioning of CpGs or their methylation levels. Anti-correlation between CpG density and methylation level is however similarly strong in both regions. On promoters, nucleosome occupancy is more strongly affected by the level of gene expression than CpG density or CpG methylation—calling into question any direct causal relation between nucleosome occupancy and CpG organization. Rather, our results suggest that for organisms with cytosine methylation nucleosome occupancy might be primarily linked to gene expression, with no strong impact on methylation.
Highlights
In eukaryotes, a large number of epigenetic mechanisms are involved in packaging the genome in different chromatin states
The majority of CpG sites is unmethylated and the methylation level drops to a minimum of approximately 0.15 per CpG site close to the transcription start site (TSS)
The methylation level drops around the TSS, a feature that is accompanied by simultaneously increasing CpG density
Summary
A large number of epigenetic mechanisms are involved in packaging the genome in different chromatin states These chromatin states provide information about gene function and cellular state (Bernstein et al, 2007; Mikkelsen et al, 2007). Nucleosome occupancy and DNA methylation, have been reported to form specific patterns around promoters and these patterns were shown to correlate with gene expression (Portela and Esteller, 2010). DNA methylation in eukaryotes mainly concerns CpG sites (Jaenisch and Bird, 2003; Antequera, 2007; Portela and Esteller, 2010), which are predominantly methylated and sparsely distributed over the genome (Gardiner-Garden and Frommer, 1987; Larsen et al, 1992; Antequera, 2007). DNA methylation is generally anti-correlated with CpG density (Lövkvist et al, 2016), i.e., in regions where CpG density is high, average methylation levels are low, and vice versa
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