Spatial organization of CpG sites determines epigenetic fidelity
Cecilia Lövkvist, Center for Models of Life, Niels Bohr Institute
The human genome contains approximately 27 million CpG sites and 60% of them are methylated. Clusters of methylated CpG sites that are overlapping promoter regions reduce gene expression. Methylation patterns are inherited and maintained through many cell divisions and this thereby preserves the epigenetic state of the cell. We aim to understand the influence of the CpG locations on methylation pattern. Previous studies of epigenomes consider mean methylation and CpG density while no focus has been on the distribution function of methylation and the geometry of the CpG site arrangement.
With current increasing amounts of data freely available we analyze 16 epigenomes from methylomeDB. First we find the CpGs to not be randomly distributed in the genome, second, their spatial organization affects the distribution of methylation level. We find an intermediate cluster size of CpGs that determines the peak of epigenetic fluctuation, i.e. lack of fidelity, with possible implications for cell differentiation. We propose a model consistent with the data for the existence of collaboration between CpGs. This collaboration increasingly polarizes the methylation with increasing numbers of adjacent CpGs while fewer adjacent CpGs are weakly interacting. From the data and our model we conclude that the collaboration between the CpGs determines under which conditions the distribution of methylation is bistable.