Abstract
Methylation at the 5 position of cytosine in DNA (5meC) is a key epigenetic mark in eukaryotes. Once introduced, 5meC can be maintained through DNA replication by the activity of ‘maintenance’ DNA methyltransferases (DNMTs). Despite their ancient origin, DNA methylation pathways differ widely across animals, such that 5meC is either confined to transcribed genes or lost altogether in several lineages. We used comparative epigenomics to investigate the evolution of DNA methylation. Although the model nematode Caenorhabditis elegans lacks DNA methylation, more basal nematodes retain cytosine DNA methylation, which is targeted to repeat loci. We found that DNA methylation coevolved with the DNA alkylation repair enzyme ALKB2 across eukaryotes. In addition, we found that DNMTs introduced the toxic lesion 3-methylcytosine into DNA both in vitro and in vivo. Alkylation damage is therefore intrinsically associated with DNMT activity, and this may promote the loss of DNA methylation in many species.
Highlights
Methylation at the 5 position of cytosine in DNA (5meC) is a key epigenetic mark in eukaryotes
Consistent with previous analyses of individual species[12,13], we found that the cytosine DNA methyltransferases (DNMTs) DNMT1 and DNMT3 have been retained in early-branching lineages, confirming that they are ancestral to nematodes
C. elegans and other nematodes lost their DNA methylation system, other nematode species contain combinations of DNMTs homologous to the mammalian DNMT1 and DNMT3 enzymes that install genomic DNA methylation in these species
Summary
Methylation at the 5 position of cytosine in DNA (5meC) is a key epigenetic mark in eukaryotes. 5meC acts as an epigenetic modification, which, once introduced by de novo methyltransferases (DNMT3a and DNMT3b in mammals), can be maintained through cell division by the activity of maintenance methyltransferases (DNMT1 in mammals)[2] Both de novo and maintenance methylation are conserved in many species across eukaryotes, including animals, plants and fungi[3,4]. In many species, including the model organisms Drosophila melanogaster, C. elegans and Saccharomyces cerevisiae, cytosine DNA methylation has been lost altogether[5,10] The factors driving such rapid evolution of DNA methylation pathways and their targets remain unclear. We found that DNMTs are the major endogenous source of the alkylation 3-methylcytosine (3meC) lesion in cells We hypothesize that this toxic activity may act to promote the loss of DNA methylation altogether in multiple lineages
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