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.

Preferentially Paternal Origin of De Novo 11p13 Chromosome Deletions Revealed in Patients with Congenital Aniridia and WAGR Syndrome

“…In this short timespan, asynchronous processes of epigenetic reprogramming of chromosomes of different parental origin occur [28]. Initially, paternal loci actively and rapidly lose CpG methylation before replication, and after that, maternal loci undergo passive demethylation during replication [29]. Demethylation in paternal DNA occurs via a base excision repair mechanism and is supposed to be linked to DNA breaks [30,31].…”

Mapping chromatin modifications at the single cell level

“…First, bisulfite treatment reduces all possible cytosine modifications to one of two states: converted or unconverted. Specifically, both 5mC and 5hmC, which can have opposing effects on gene expression (Zhu et al, 2018), are protected from conversion (Huang et al, 2010), whereas C, 5fC and 5caC are substrates for conversion. Second, bisulfite treatment is harsh: because conversion is much more efficient on single-stranded versus double-stranded DNA (Shapiro et al, 1974), the required acidic conditions and high temperatures ultimately degrade approximately 90% of the input DNA (Grunau et al, 2001).…”

“…Whereas 5mC and, to a lesser extent, 5hmC are stable, 5fC and 5caC are more transient. Currently, there is debate as to whether these less stable modifications play a functional role beyond serving as intermediates in the active demethylation pathway Zhu et al, 2018).…”

Advances and Current Challenges Associated with the Use of Human Induced Pluripotent Stem Cells in Modeling Neurodegenerative Disease

“…Epigenetic silencing is especially important to consider when stem cells differentiate as the epigenetic switching of genes "on" or "off" is important in the regulation of cell fate [Ficz et al, 2011;Tao et al, 2018;Zhu et al, 2018]. This allows cells to develop distinct identities while maintaining a common genetic code.…”