A Lexicon of DNA Modifications: Their Roles in Embryo Development and the Germline

Abstract

5-methylcytosine (5mC) on CpG dinucleotides has been viewed as the major epigenetic modification in eukaryotes for a long time. Apart from 5mC, additional DNA modifications have been discovered in eukaryotic genomes. Many of these modifications are thought to be solely associated with DNA damage. However, growing evidence indicates that some base modifications, namely 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxylcytosine (5caC), and N6-methadenine (6mA), may be of biological relevance, particularly during early stages of embryo development. Although abundance of these DNA modifications in eukaryotic genomes can be low, there are suggestions that they cooperate with other epigenetic markers to affect DNA-protein interactions, gene expression, defense of genome stability and epigenetic inheritance. Little is still known about their distribution in different tissues and their functions during key stages of the animal lifecycle. This review discusses current knowledge and future perspectives of these novel DNA modifications in the mammalian genome with a focus on their dynamic distribution during early embryonic development and their potential function in epigenetic inheritance through the germ line.

Keywords: 5hmC; 5mC; 6mA; embryo; epigenetic reprogramming; germ cells; modified bases in eukaryotic DNA.

Figure 1

DNA methylation in the mammalian lifecycle DNA methylation profiles show differences in the lifecycle of different mammals. They are most dynamic during the epigenetic reprogramming in preimplantation embryo and primordial germ cells (PGCs). 5mC is largely erased during both epigenetic reprogramming events in the pre-implantation embryo and germ cells and subsequently re-established. Methylation reprogramming in PGCs is more extensive than in early embryo, including demethylation of imprinted genes and repetitive elements. 5hmC, 5fC and 5caC are the oxidized products of TET-mediated active demethylation. Timing and extent of TET-mediated active demethylation differ between genders in pre-implantation embryos and in PGCs of different species. 6mA is found enriched in pig oocytes and early embryos. The epigenome is much more vulnerable to environmental influences, especially during the extensive remodeling phases, which may lead to abnormal epigenetic states in the embryo and germline that contribute to future development and inheritance of disease.