Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification

  title={Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification},
  author={Lakshminarayan M. Iyer and Dapeng Zhang and L. Aravind},
  pages={27 - 40}
While N6‐methyladenosine (m6A) is a well‐known epigenetic modification in bacterial DNA, it remained largely unstudied in eukaryotes. Recent studies have brought to fore its potential epigenetic role across diverse eukaryotes with biological consequences, which are distinct and possibly even opposite to the well‐studied 5‐methylcytosine mark. Adenine methyltransferases appear to have been independently acquired by eukaryotes on at least 13 occasions from prokaryotic restriction‐modification and… 

Epigenetic Methylations on N6-Adenine and N6-Adenosine with the same Input but Different Output

The latest progress in the study of enzymes involved in the 6mA and m6A methylation machinery, including methyltransferases and demethylases, and their functions in various biological pathways are summarized.

Reconstitution of eukaryotic chromosomes and manipulation of DNA N6-methyladenine alters chromatin and gene expression

A novel DNA 6mA methyltransferase in ciliates, termed MTA1, contains an MT-A70 domain but is phylogenetically distinct from all known RNA and DNA methyltransferases, and defines the impact of 6mA on chromatin organization using epigenetically defined synthetic chromosomes.

A distinct class of eukaryotic MT-A70 methyltransferases maintain symmetric DNA N6-adenine methylation at the ApT dinucleotides as an epigenetic mark associated with transcription

The results support that AMT1-catalyzed 6mA is an integral part of the transcription-associated epigenetic landscape and may have implications in eukaryotic diversification.

CG14906 (mettl4) mediates m6A methylation of U2 snRNA in Drosophila

Enhanced crosslinking and immunoprecipitation (IP) followed by high-throughput sequencing (eCLIP-seq), which was originally developed to map binding sites of RNA-binding proteins on their target RNAs, was performed to identify the RNA type that is targeted by mettl4 in vivo.

Epigenetics of Modified DNA Bases: 5-Methylcytosine and Beyond

The most recently discovered N6-methyladenine, an additional epigenetic mark with regulatory potential, is also described, Interestingly, these newly discovered modifications are also found in the genomes which lack canonical 5-mC, signifying their independent epigenetic functions.

TET methylcytosine oxidases: new insights from a decade of research

The puzzle of whether DNA methylation was reversible remained unclear for many decades until the discovery of the TET (Ten-Eleven Translocation) family of 5-methylcytosine oxidases, which use reduced iron, molecular oxygen and the tricarboxylic acid cycle metabolite 2-oxoglutarate to oxidise the methyl group of 5mC to 5-hydroxymethylcyTosine (5hmC) and beyond.

Cap-specific, terminal N6-methylation by a mammalian m6Am methyltransferase

PCIF1 was originally identified and named due to its ability to directly bind to the phosphorylated C-terminal domain of RNA polymerase II via its WW domain; hence it was speculated to play a role in mRNA biogenesis; however, no enzymatic activity has been reported for PCIF1.

TET family dioxygenases and DNA demethylation in stem cells and cancers

Recent advances in the mechanistic understanding of DNA methylation–demethylation dynamics, and their potential regulatory functions in cellular differentiation and oncogenic transformation are focused on.



Natural history of eukaryotic DNA methylation systems.

Natural history of the eukaryotic chromatin protein methylation system.

Protein and DNA modifications: evolutionary imprints of bacterial biochemical diversification and geochemistry on the provenance of eukaryotic epigenetics.

Developments in comparative genomics show that key components of eukaryotic epigenetics emerged as part of the extensive biochemical innovation of secondary metabolism and intergenomic/interorganismal conflict systems in prokaryotes, particularly bacteria.

Biochemical characterization of a Naegleria TET-like oxygenase and its application in single molecule sequencing of 5-methylcytosine

NgTET1 is a 5-methylpyrimidine oxygenase, with activity on both 5mC (major activity) and thymidine (T) (minor activity) in all DNA forms tested, and provide unprecedented evidence for the formation of 5-formyluridine (5fU) and 5-carboxyuridine(5caU) in vitro.

Structure and function of DNA methyltransferases.

  • X. Cheng
  • Biology, Chemistry
    Annual review of biophysics and biomolecular structure
  • 1995
Structural work on HhaI DNA methyltransferase demonstrates that the substrate nucleotide is completely flipped out of the helix during the modification reaction and has provided much insight into the enzymatic properties of S-adenosyl-L-methionine (SAM)-dependent DNA-modifying enzymes.

Structure, function and mechanism of exocyclic DNA methyltransferases.

Being nucleotide-sequence-specific, DNA MTases provide excellent model systems for studies on protein-DNA interactions and could therefore be used as delivery systems for fluorescent or other reporter groups on to DNA.

Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq

The findings suggest that RNA decoration by m6A has a fundamental role in regulation of gene expression, and a subset of stimulus-dependent, dynamically modulated sites is identified.

Genome-Wide Evolutionary Analysis of Eukaryotic DNA Methylation

The data suggest that land plants and vertebrates are under strong selective pressure to repress TEs, because of their sexual mode of reproduction, and indicate that gene body methylation is an ancient property of eukaryotic genomes.

Simultaneous sequencing of oxidized methylcytosines produced by TET/JBP dioxygenases in Coprinopsis cinerea

The study provides evidence for the emergence of an epigenetic regulatory system through recruitment of selfish elements in a eukaryotic lineage and describes a method for simultaneous mapping of the three different species of oxi-mCs at near–base-pair resolution.

Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1

It is shown here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro.