Natural history of the eukaryotic chromatin protein methylation system.

In eukaryotes, methylation of nucleosomal histones and other nuclear proteins is a central aspect of chromatin structure and dynamics. The past 15 years have seen an enormous advance in our understanding of the biochemistry of these modifications, and of their role in establishing the epigenetic code. We provide a synthetic overview, from an evolutionary perspective, of the main players in the eukaryotic chromatin protein methylation system, with an emphasis on catalytic domains. Several components of the eukaryotic protein methylation system had their origins in bacteria. In particular, the Rossmann fold protein methylases (PRMTs and DOT1), and the LSD1 and jumonji-related demethylases and oxidases, appear to have emerged in the context of bacterial peptide methylation and hydroxylation systems. These systems were originally involved in synthesis of peptide secondary metabolites, such as antibiotics, toxins, and siderophores. The peptidylarginine deiminases appear to have been acquired by animals from bacterial enzymes that modify cell-surface proteins. SET domain methylases, which display the β-clip fold, apparently first emerged in prokaryotes from the SAF superfamily of carbohydrate-binding domains. However, even in bacteria, a subset of the SET domains might have evolved a chromatin-related role in conjunction with a BAF60a/b-like SWIB domain protein and topoisomerases. By the time of the last eukaryotic common ancestor, multiple SET and PRMT methylases were already in place and are likely to have mediated methylation at the H3K4, H3K9, H3K36, and H4K20 positions, and carried out both asymmetric and symmetric arginine dimethylation. Inference of H3K27 methylation in the ancestral eukaryote appears uncertain, though it was certainly in place a little later in eukaryotic evolution. Current data suggest that unlike SET methylases, which are universally present in eukaryotes, demethylases are not. They appear to be absent in the earliest-branching eukaryotic lineages, and emerged later along with several other chromatin proteins, such as the Dot1-methylase, prior to divergence of the kinetoplastid-heterolobosean lineage from the remaining eukaryotes. This period also corresponds to the point of origin of DNA cytosine methylation by DNMT1. Origin of major lineages of SET domains such as the Trithorax, Su(var)3-9, Ash1, SMYD, and TTLL12 and E(Z) might have played the initial role in the establishment of multiple distinct heterochromatic and euchromatic states that are likely to have been present, in some form, through much of eukaryotic evolution. Elaboration of these chromatin states might have gone hand-in-hand with acquisition of multiple jumonji-related and LSD1-like demethylases, and functional linkages with the DNA methylation and RNAi systems. Throughout eukaryotic evolution, there were several lineage-specific expansions of SET domain proteins, which might be related to a special transcription regulation process in trypanosomes, acquisition of new meiotic recombination hotspots in animals, and methylation and associated modifications of the diatom silaffin proteins involved in silica biomineralization. The use of specific domains to "read" the methylation marks appears to have been present in the ancestral eukaryote itself. Of these the chromo-like domains appear to have been acquired from bacterial secreted proteins that might have a role in binding cell-surface peptides or peptidoglycan. Domain architectures of the primary enzymes involved in the eukaryotic protein methylation system indicate key features relating to interactions with each other and other modifications in chromatin, such as acetylation. They also emphasize the profound functional distinction between the role of demethylation and deacetylation in regulation of chromatin dynamics.