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Adenine DNA methylation associated to transcription is widespread across eukaryotes

Pedro Romero Charria, Cristina Navarrete, Vladimir Ovchinnikov, Luke A Sarre, Victoria Shabardina, Elena Casacuberta, David Lara-Astiaso, Arnau Sebé-Pedrós, Alex de Mendoza

Posted on: 13 January 2025 , updated on: 14 January 2025

Preprint posted on 28 October 2024

Breaking paradigms: Finding 6mA DNA methylation in eukaryotes.

Selected by Francisco Falcon

Background

Chemical modifications on DNA are a common occurrence in most organisms. These modifications can have various impacts on both gene regulation and genome organization. While the methylation of the 5-carbon position of the cytosine nucleotide (5mC) is probably the most studied modification in eukaryotes, the presence of other modifications has always been a topic for debate and speculation.

In this preprint from Romero-Charria and colleagues, the authors make use of recent advancements of the Oxford Nanopore sequencing platform to answer—in a very comprehensive manner—whether 6mA (N6 methyladenine), a DNA modification common in bacteria, is present in eukaryotes.

Since 6mA is not well-studied in eukaryotes, the authors looked to find the source of this DNA modification, its genomic distribution, and possible roles that it could have in gene regulation.

Key findings

  • The authors first identified the gene AMT1 as the potential source of 6mA DNA methylation in eukaryotes by describing the evolution of MTA-70 methyltransferases.
  • By sequencing different species under conditions that excluded other sources of DNA contamination, the authors linked the presence of AMT1 to the presence of 6mA in various organisms representing different eukaryotic groups (Figure 2a).
Figure 2a from the preprint – Levels of 6mA methylation detected on species that conserve the AMT1.
  • The authors described that 5mC and 6mA are not linked functionally, and that transcriptionally active genes tend to have higher levels of 6mA.
  • Nucleosomes containing the H3K3me3 tended to also have 6mA modifications and provide a hypothesis on how the epigenome of the last eukaryotic common ancestor was regulated through different DNA modifications (Figure 5).

Figure 5 from the preprint – Reconstruction of the epigenome of the last eukaryotic common ancestor, as well as the current epigenome of different extant taxa in terms of DNA modifications.

Why is this paper important?

In this study the authors make good use of an emerging technology to address the long-standing question of whether 6mA is widespread throughout the tree of life. This work also offers insights into the evolution of gene regulation, as it seems that this modification was lost in eukaryotes.

Personally, I relate to this preprint as we work often with Nanopore sequencing, and it is quite exciting to see the possibilities this technology brings not just in terms of genome assembly, but also to study nucleic acid modifications in such elegant and reliable manner. Another aspect I am quite fond of is the effort the authors took to uncover the ancestral state of the eukaryotic common ancestor, something I am working on in my day to day, although in a smaller evolutionary scale.

Tags: dna methylation, m6a

doi: https://doi.org/10.1242/prelights.39131

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Author's response

Alex de Mendoza shared

1.- Transposable element control is quite important in many species that make use of 5mC to silence them. Do you envision that there are any species where AMT1 is present and that this could be associated with a higher transposable element content?
That’s the intriguing contrast between 5mC and 6mA. While 5mC is quite labile and has evolved into multiple roles and patterns across the eukaryotes, 6mA seems more restricted to transcriptionally active chromatin. But just because 6mA is associated with transcription, transposable elements might benefit from trying to actively be targeted by this modification in order to keep transcribing. Probably finer grain detail analysis could reveal some of these cases, although in general, TEs are depleted for 6mA. How does this correlate with transposon load in the genome, we still don’t know. Our set of species with AMT1-6mA goes from tiny genomes with virtually no repeats (e.g. Ostreococcus) to Trichomonas, whose genome is 1/3 made of very large Maverick transposons.
2.- In the discussion section, you mention the possible existence of 6mA readers. Following a similar process to find AMT1, do you see members of the YTH readers being expanded or lost in species with 6mA?
The presence / absence of YTH does not correlate well with genomic  6mA / AMT1. However, it does correlate with METTL3/14, which are  enzymes of the same family of AMT1, but are responsible for RNA modifications. This suggests that YTH are probably restricted to reading m6A (the RNA form of adenine methylation). One of the follow up projects we want to chase if to try to identify DNA 6mA readers.
3.-Do you have any insight into how AMT1 is recruited to its target sites?
Previous work on ciliates (https://pubmed.ncbi.nlm.nih.gov/31104845/) indicates that AMT1 requires a couple small DNA binding proteins named p1 and p2 to bind and methylate adenines. However, what targets p1, p2 and AMT1 to the patterns we see in the genome, is still not clear. Our guess is that there must be a cross-talk with H3K4me3,  as these two epigenomic marks correlate very well. Perhaps the histone modification enables or attracts the AMT1 complex to these regions. Since H3K4me3 is more evolutionary stable and widespread across the eukaryotes, this would argue in favour of a model where H3K4me3 is upstream of 6mA, since it would have been hard for so many lineages to find new ways to targeting H3K4me3 when 6mA was lost. But we still don’t know for certain.

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