Exploring the Link between Nucleosome Occupancy and DNA Methylation

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.

Targeted profiling of human extrachromosomal DNA by CRISPR-CATCH

“…The four regions that lost 5mC on ecDNA compared to its chromosomal locus in the same cells were all gene promoters, including that of the EGFR oncogene (Methods, Figure 3d,e, Extended Data Figure 2b). The pattern of hypomethylation corresponded to nucleosome positions shown by MNase-seq, implying a more active chromatin state on ecDNA (Figure 3e, Extended Data Figure 2c) 19,20 . Finally, single-molecule analysis of purified ecDNA at the EGFR promoter showed hypomethylation at the EGFR promoter and co-occurrence of methylation spanning hundreds of CpG sites around the region on the same molecules (285 CpG sites, Figure 3f).…”

Biological embedding of experience: A primer on epigenetics

“…Epigenetic mechanisms function in concert within a cell and may interact with each other (122,123). Thus, a systems level approach is needed to understand the biological embedding of experience.…”

Utility of cfDNA Fragmentation Patterns in Designing the Liquid Biopsy Profiling Panels to Improve Their Sensitivity

“…Nevertheless, the overall robustness of nucleosome positioning remains unclear. It is known that several regulatory events defining the gene expression require the strict positioning of nucleosomes; these events are typically associated with promoter regions ( Hesson et al, 2014 ; Lövkvist et al, 2018 ). However, nucleosome positioning is not absolute, and even with major shifts in gene expression, some cells fail to change nucleosome configuration ( Small et al, 2014 ), thus, indicating an underlying complexity of nucleosome positioning.…”