Conserved and divergent patterns of DNA methylation in higher vertebrates.
Bottom Line: DNA methylation in the genome plays a fundamental role in the regulation of gene expression and is widespread in the genome of eukaryotic species.For example, in higher vertebrates, there is a "global" methylation pattern involving complete methylation of CpG sites genome-wide, except in promoter regions that are typically enriched for CpG dinucleotides, or so called "CpG islands." Here, we comprehensively examined and compared the distribution of CpG sites within ten model eukaryotic species and linked the observed patterns to the role of DNA methylation in controlling gene transcription.Comparative analysis with four other higher vertebrates revealed that the primary regulatory role of the DNA methylation system is highly conserved in higher vertebrates.
Affiliation: Department of Biostatistics & Computational Biology, SKLG, School of Life Sciences, Fudan University, Shanghai, China School of Biosciences, The University of Birmingham, Birmingham B15 2TT United Kingdom.Show MeSH
Mentions: We analyzed genome-wide DNA methylation profiles from 28 different human tissues (or cell lines), which were assayed by the Illumina Human Methylation27 BeadChip platform (Bonazzi et al. 2011; Chari et al. 2011; Loudin et al. 2011). This BeadChip assessed 27,578 CpG sites located within the promoter regions of 14,475 genes. Multiple sites (on average, two CpGs) were interrogated per promoter region. We confirmed that CpG sites have much lower methylation levels in promoter regions when compared with the genome-wide average, as previously shown (Lister et al. 2009). Figure 5A shows a slightly bimodal distribution: The majority (72.7%) of CpG sites in all promoter regions across 28 tissues were unmethylated (methylation level ≤ 0.1), whereas 18.5% were semimethylated (methylation level between 0.1 and 0.7) and 8.8% were considered methylated (methylation level ≥ 0.7), according to the criteria established in Bell et al. (2011). The distribution of methylation levels showed two distinct patterns for HCP compared with LCP (fig. 5B). The HCP showed a unimodal distribution, with 77.1% unmethylated, 16.6% semimethylated and 6.3% methylated CpG sites, whereas the CpG sites in LCP tended to be more highly methylated, with corresponding proportions of 25.8%, 37.9% and 36.3%. Both HCP and LCP showed a similar distribution of methylation levels with respect to distance from the TSS (fig. 5C). The lowest methylation levels are found in the vicinity of the TSS, whereas the methylation level increases with increasing distance from the TSS. However, CpG sites in the LCP showed consistently higher methylation levels than those in the HCP throughout the promoter region. Within an individual promoter, the methylation levels of adjacent CpG pairs were positively correlated, and the correlation tends to be weakened when the CpG pairs are distantly separated (fig. 5D). Moreover, the CpG pairs within LCP exhibited a higher correlation in methylation levels compared with HCP across all distances.Fig. 5.—
Affiliation: Department of Biostatistics & Computational Biology, SKLG, School of Life Sciences, Fudan University, Shanghai, China School of Biosciences, The University of Birmingham, Birmingham B15 2TT United Kingdom.