Abstract
BackgroundDNA methylation is an epigenetic modification that is enriched in heterochromatin but depleted at active promoters and enhancers. However, the debate on whether or not DNA methylation is a reliable indicator of high nucleosome occupancy has not been settled. For example, the methylation levels of DNA flanking CTCF sites are higher in linker DNA than in nucleosomal DNA, while other studies have shown that the nucleosome core is the preferred site of methylation. In this study, we make progress toward understanding these conflicting phenomena by implementing a bioinformatics approach that combines MNase-seq and NOMe-seq data and by comprehensively profiling DNA methylation and nucleosome occupancy throughout the human genome.ResultsThe results demonstrated that increasing methylated CpG density is correlated with nucleosome occupancy in the total genome and within nearly all subgenomic regions. Features with elevated methylated CpG density such as exons, SINE-Alu sequences, H3K36-trimethylated peaks, and methylated CpG islands are among the highest nucleosome occupied elements in the genome, while some of the lowest occupancies are displayed by unmethylated CpG islands and unmethylated transcription factor binding sites. Additionally, outside of CpG islands, the density of CpGs within nucleosomes was shown to be important for the nucleosomal location of DNA methylation with low CpG frequencies favoring linker methylation and high CpG frequencies favoring core particle methylation. Prominent exceptions to the correlations between methylated CpG density and nucleosome occupancy include CpG islands marked by H3K27me3 and CpG-poor heterochromatin marked by H3K9me3, and these modifications, along with DNA methylation, distinguish the major silencing mechanisms of the human epigenome.ConclusionsThus, the relationship between DNA methylation and nucleosome occupancy is influenced by the density of methylated CpG dinucleotides and by other epigenomic components in chromatin.
Highlights
DNA methylation is an epigenetic modification that is enriched in heterochromatin but depleted at active promoters and enhancers
Using the flanking DNA centered on nucleosome midpoints, the sequence content, DNA methylation levels, and nucleosome occupancies were measured for the entire genome and for several subgenomic regions
In order to compare DNA methylation patterns derived from nucleosomes reconstituted in vitro to those formed in the cell, BS-seq [32] and MNase-seq [33], data derived from leukocytes were used (Fig. 1a–f )
Summary
DNA methylation is an epigenetic modification that is enriched in heterochromatin but depleted at active promoters and enhancers. The debate on whether or not DNA methylation is a reliable indicator of high nucleosome occupancy has not been settled. We make progress toward understanding these conflicting phenomena by implementing a bioinformatics approach that combines MNase-seq and NOMe-seq data and by comprehensively profiling DNA methylation and nucleosome occupancy throughout the human genome. At the primary level of chromatin compaction, a 147-base-pair segment of DNA spirals nearly twice around an octamer of histone proteins to form a structure known as the nucleosome [1, 2]. Nucleosomedepleted regions are observed overlapping transcription start sites of active genes, while high nucleosome occupancy is found to encompass the promoters of silent genes [5]. Several genome‐wide explorations in conjunction with biochemical modifications have
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