Abstract
DNA methylation is one of the most important epigenetic modifications and is closely related with several biological processes such as regulation of gene transcription and the development of non-malignant diseases. The prevailing dogma states that DNA methylation in eukaryotes occurs essentially through 5-methylcytosine (5mC) but recently adenine methylation was also found to be present in eukaryotes. In mouse embryonic stem cells, 6-methyladenine (6mA) was associated with the repression and silencing of genes, particularly in the X-chromosome, known to play an important role in cell fate determination. Here, we have demonstrated that 6mA is a ubiquitous eukaryotic epigenetic modification that is put in place during epigenetically sensitive periods such as embryogenesis and fetal development. In somatic cells there are clear tissue specificity in 6mA levels, with the highest 6mA levels being observed in the brain. In zebrafish, during the first 120 h of embryo development, from a single pluripotent cell to an almost fully formed individual, 6mA levels steadily increase. An identical pattern was observed over embryonic days 7–21 in the mouse. Furthermore, exposure to a neurotoxic environmental pollutant during the same early life period may led to a decrease in the levels of this modification in female rats. The identification of the periods during which 6mA epigenetic marks are put in place increases our understanding of this mammalian epigenetic modification, and raises the possibility that it may be associated with developmental processes.
Highlights
It is known to occur in both cytosine and adenine bases, the prevailing dogma is that DNA methylation essentially occurs on the fifth position of cytosine residues. 5-methylcytosine (5mC) is an evolutionarily conserved modification, present throughout both eukaryotes to prokaryotes, which is involved in the development and afterward adaptation to the local environment (LaSalle, 2011; Bonsch et al, 2012; Tobi et al, 2018)
The time to perform the test was significantly decreased in controls when compared to the first trial, (p < 0.05), showing animals learned the task, that became a trend in the 22 ng/kg/day α-HBCDD-exposed animals (p = 0.09) and there was no difference at the highest dose (Supplementary Figure 4C), confirming that α-HBCDD exposure induced learning deficits, and the same pattern was observed for the number of missteps, confirming that motor deficits were induced
Epigenetic modifications are known to occur in RNA, DNA and histones and, they may change the accessibility of the DNA region and/or gene expression, the original DNA sequence remains unaltered (Robin, 1989)
Summary
It is known to occur in both cytosine and adenine bases, the prevailing dogma is that DNA methylation essentially occurs on the fifth position of cytosine residues. 5-methylcytosine (5mC) is an evolutionarily conserved modification, present throughout both eukaryotes to prokaryotes, which is involved in the development and afterward adaptation to the local environment (LaSalle, 2011; Bonsch et al, 2012; Tobi et al, 2018). Gene ontology analysis showed that in the stress model, 6mA levels negatively correlate with neuronal gene expression and the differentially methylated genes overlap with genes present in mental disorders such as depression and autism (Yao et al, 2017) and in the embryonic stem cell model, LINE1 element methylation impacted their transcription as well as in their neighboring genes (Wu et al, 2016) This is contradicted by Xiao who observed significantly higher levels of 6mA in the mitochondria rather than on the genome per se (0.18% vs 0.055%), and Koziol et al (2016) who reported 6mA in non-coding regions of the genome. These results may help shed a light on our understanding of the mammalian epigenetic modifications
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