Genome-wide and single-base resolution DNA methylomes of the Sea Lamprey (Petromyzon marinus) Reveal Gradual Transition of the Genomic Methylation Pattern in Early Vertebrates
In eukaryotes, cytosine methylation is a primary heritable epigenetic modification of the genome that regulates many cellular processes. While the whole-genome methylation pattern has been generally conserved in different eukaryotic groups, invertebrates and vertebrates exhibit two distinct patterns. Whereas almost all CpG sites are methylated in most vertebrates, with the exception of short unmethylated regions call CpG islands, the most frequent pattern in invertebrate animals is mosaic methylation, comprising domains of heavily methylated DNA interspersed with domains that are methylation free. The mechanism by which the genome methylation pattern transited from a mosaic to a global pattern and the role of the one or two-round whole-genome duplication in this transition remain largely elusive, partly owing to the lack of methylome data from early vertebrates. In this study, we used the whole-genome bisulfite-sequencing technology to investigate the genome-wide methylation in three tissues (heart, muscle, and sperm) from the sea lamprey, an extant Agarthan vertebrate. Analyses of methylation level and the extent of CpG dinucleotide depletion of geneencoding, intergenic and promoter regions revealed a gradual increase in the methylation level from invertebrates to vertebrates, with the sea lamprey exhibiting an intermediate position. In addition, the methylation level of the majority of CpGs was intermediate in each sea lamprey tissue, indicating a high level of heterogeneity of methylation status between individual cells. In this regard, we defined the genomic methylation pattern of sea lamprey as \"global genomic DNA intermediate methylation\". The methylation features in different genomic regions, such as the transcription start site (TSS) region of the gene body, exon-intron boundaries, transposons, as well as genes grouping with different expression levels, supported the gradual methylation transition hypothesis. We further discussed that the copy number difference in DNA methylation transferases and the loss of the PWWP domain and/or DNTase domain in DNMT3 sub-family enzymes may have contributed to the methylation pattern transition in early vertebrates. These findings demonstrate an intermediate genomic methylation pattern between invertebrates and jawed vertebrates, providing evidence that supports the hypothesis that methylation patterns underwent a gradual transition from invertebrates (mosaic) to vertebrates (global).