The DNA methylome

Abstract

Methylation of cytosines is a pervasive feature of eukaryotic genomes and an important epigenetic layer that is fundamental for cellular differentiation processes and control of transcriptional potential. DNA methylation patterns can be inherited and influenced by the environment, diet and aging, and disrupted in diseases. Complete DNA methylomes for several organisms are now available, helping clarify the evolutionary story of this epigenetic mark and its distribution in key genomic elements. Nonetheless, a complete understanding of its role, the mechanisms responsible for its establishment and maintenance, and its cross talk with other components of cellular machinery remains elusive.

Fig. 1

Methylation levels in 23 eukaryotic organisms. The organisms are organized according to their evolutionary distance. Tree topology is determined from the NCBI Taxonomy (http://www.ncbi.nlm.nih.gov/guide/taxonomy/) and displayed using TreeView X (http://darwin.zoology.gla.ac.uk/~rpage/treeviewx/index.html). The genome size is indicated together with the percentage of methylated sites within three sequence contexts: CpG, CHG and CHH (H being A, C or T).

Fig. 2

Pitfalls in the analysis of DNA methylomes. (A) MeDIP-chip enrichment is not linearly related to the DNA methylation level (graph created using MEDME [10]). (B) The mC calls determined for two samples with different sequencing depth; the height of the bars corresponds to the methylation level (the proportion of methylated over total reads for a given cytosine); a differentially methylated region can be improperly identified if the depth is not considered; in addition higher methylation levels could be computed in the sample with lower coverage. (C) two promoters with the same number of mC but different density of available methylation sites (LCP and HCP : low and high CpG content promoter, respectively); the increase of mC from 2 to 10 in the two promoters can have remarkably different effect on the transcription of the downstream gene (TSS: transcriptional start site; CGI: CpG island). (D) signal and signal-to-noise for enrichment methods (MeDIP-seq) and for bisulfite sequencing methods (MethylC-Seq); RE is a repetitive region that cannot be covered.