Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Dec 18:9:640.
doi: 10.3389/fgene.2018.00640. eCollection 2018.

Epigenetics of Modified DNA Bases: 5-Methylcytosine and Beyond

Suresh Kumar  1 , Viswanathan Chinnusamy  2 , Trilochan Mohapatra  3
Affiliations
Review

Epigenetics of Modified DNA Bases: 5-Methylcytosine and Beyond

Suresh Kumar et al. Front Genet. .

Abstract

Modification of DNA bases plays vital roles in the epigenetic control of gene expression in both animals and plants. Though much attention is given to the conventional epigenetic signature 5-methylcytosine (5-mC), the field of epigenetics is attracting increased scientific interest through the discovery of additional modifications of DNA bases and their roles in controlling gene expression. Theoretically, each of the DNA bases can be modified; however, modifications of cytosine and adenine only are known so far. This review focuses on the recent findings of the well-studied cytosine modifications and yet poorly characterized adenine modification which serve as an additional layer of epigenetic regulation in animals and discuss their potential roles in plants. Cytosine modification at symmetric (CG, CHG) and asymmetric (CHH) contexts is a key epigenetic feature. In addition to the ROS1 family mediated demethylation, Ten-Eleven Translocation family proteins-mediated hydroxylation of 5-mC to 5-hydroxymethylcytosine as additional active demethylation pathway are also discussed. The epigenetic marks are known to be associated with the regulation of several cellular and developmental processes, pluripotency of stem cells, neuron cell development, and tumor development in animals. Therefore, 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. These modified DNA bases are considered to be important players in epigenomics. The potential for combinatorial interaction among the known modified DNA bases suggests that epigenetic codon is likely to be substantially more complicated than it is thought today.

Keywords: 5-hydroxymethylcytosine; 5-methylcytosine; DNA modification; N6-methyladenine; cytosine methylation; epigenetic marks; modified DNA base.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Cytosine modifications and active demethylation pathway in animal system. Cytosine is converted to 5-methylcytosine (5-mC) by DNA methyltransferase. By the action of DNA demethylase, 5-mC may get converted back to cytosine (C). Tet oxidase (Tet-1, Tet-2, or Tet-3) oxidize 5-mC to 5-hydroxymethylcytosine (5-hmC). 5-hmC can be further oxidized by Tet oxidase to 5-formylcytosine (5-fC) and subsequently to 5-carboxycytosine (5-caC). Finally, 5-caC and the deamination product of 5-mC [firstly thymine and then 5-hydroxymethyluracil (5-hmU)] are replaced by the cytosine via base-excision repair pathway. The upper pannel (in box), represents base-excision repair (BER) pathway for active DNA demethylation in plants. Repressor of Silencing (ROS1) and Demeter (DME) remove 5-mC and cleave the DNA backbone to generate a gap with 3′-phosphate terminus which gets converted into 3′-OH by Zinc finger DNA 3′-phosphoesterase (ZDP). The gap is finally filled with a usual cytosine (C) by an unknown DNA polymerase (?) and AtLIG1.
FIGURE 2
FIGURE 2
DNA (de)methylation dynamics. Cytosine (C) is methylated at 5′ carbon of the pyrimidine ring by DNA methyltransferases (DNMT-1, DNMT-3A, DNMT-3B), the writer, to generate 5-methylcytosine (5-mC), which is recognized by methyl-CpG binding protein 2 (MeCP2), the reader. 5-mC gets hydroxylated by Ten-Eleven Translocation 1 (TET-1, TET-2, TET-3) methylcytosine dioxygenases, the writer, to 5-hydroxymethylcytosine (5-hmC) which is recognized by ubiquitin-like PHD and Ring finger domain-containing proteins (UHRF-1, UHRF-2), the readers. 5-mC may also get deaminated by cytidine deaminase (activation-induced deaminase), the eraser, to generate 5-hydroxymethyluracil (5-hmU). Further, 5-hmC gets oxidized by TETs to 5-formylcytosine (5-fC) and then to 5-carboxylcytosine (5-caC). Finally, all of these intermediates are substrates for thymine-DNA glycosylase (TDG) and base-excision repair (BER)-mediated DNA demethylation, the eraser pathway.
FIGURE 3
FIGURE 3
Adenine modification dynamics. Adenine gets methylated by DNA N6-adenine methyltransferases (DAMT-1) to produce N6-methyladenine (6-mA), as observed in C. elegans. 6-mA can be demethylated by the action of N6-methyl adenine demethylase-1 (NMAD-1) or DNA methyladenine demethylase (DMAD). Oxidation of methyl group of 6-mA by AlkB oxidase results in the formation of N6-hydroxymethyl adenine (6-hmA) and N6-formyl adenine (6-fA), and finally back to adenine. Adenine may also get methyl adduct by endogenous or environmental alkylating agents to N1-methyladenine (1-mA), which may further get demethylated by AlkB oxidase to adenine via N1-methylhydroxy adenine (1-hmA).
FIGURE 4
FIGURE 4
Adenine (de)methylation dynamics. Adenine (A) is methylated at N6 of the purine ring by DNA N6-adenine methyltransferases 1 (DAMT-1), the writer, to generate N6-methyladenine (6-mA). SeqA protein, the reader, preferentially binds to hemimethylated (6-mA) DNA. 6-mA may get demethylated by the action of N6-methyl adenine demethylase-1 (NMAD-1) or DNA methyladenine demethylase (DMAD), the eraser.
See this image and copyright information in PMC

References

    1. Allis C. D., Jenuwein T. (2016). The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17 487–500. 10.1038/nrg.2016.59 - DOI - PubMed
    1. Avramova Z. (2015). Transcriptional “memory” of a stress: transient chromatin and memory (epigenetic) marks at stress-response genes. Plant J. 83 149–159. 10.1111/tpj.12832 - DOI - PubMed
    1. Bachman M., Uribe-Lewis S., Yang X., Williams M., Murrell A., Balasubramanian S. (2014). 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nat. Chem. 6 1049–1055. 10.1038/nchem.2064 - DOI - PMC - PubMed
    1. Baubec T., Colombo D. F., Wirbelauer C., Schmidt J., Burger L., Krebs A. R., et al. (2015). Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520 243–247. 10.1038/nature14176 - DOI - PubMed
    1. Breiling A., Lyko F. (2015). Epigenetic regulatory functions of DNA modifications: 5-methylcytosine and beyond. Epigenetics Chromatin 8:24. 10.1186/s13072-015-0016-6 - DOI - PMC - PubMed

LinkOut - more resources