DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line
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Figure 1
Basic principles of DNA methylation. (A) Schematic illustration of reversible cytosine methylation to generate 5mC. The methylation process depends on DNMTs and conversion of the methyl group donor SAM to SAH. The demethylation process can involve both passive demethylation and active demethylation processes requiring TET proteins, TDG, and BER. In the active process, 5mC can be converted to the intermediates 5hmC, 5fC and 5caC before ending up as cytosine. (B) Maintenance of DNA methylation patterns following DNA replication. As a result of DNA replication, the newly generated double-stranded DNA will be hemi-methylated with the original template strands maintaining the original methylation pattern (black strands) and the new strands without methylation (gray strands). The symmetrical nature of CpG sites ensures that hemi-methylated DNA can direct the original pattern of methylation to the new DNA through the action of DNMTs with DNMT1 considered the most prominent maintenance DNMT. A full colour version of this figure is available at https://doi.org/10.1530/JME-17-0189.
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Figure 2
Schematic mechanisms of transcriptional regulation through promoter DNA methylation. (A) For a transcriptionally active promoter, the recruitment of transcription factors (TFs) results in an open chromatin structure with relative nucleosome depletion and transcriptional coactivator (CoA) presence. This outcome is achieved through protein complexes with e.g. histone acetylase (HAT), histone methylation (HM), and histone demethylation (HDM) activities towards histone tail residues. (B) Following DNA methylation of the promoter, TF binding is hindered by blocking of the specific recognition sequences, and this resulting in decreased promoter activity. (C) Following DNA methylation of the promoter, 5mC residues recruit MeCP2 and members of the MBP family. These proteins can take part in protein complexes mediating transcriptional repression depending on histone deacetylase (HDAC), HM, and HDM activities towards histone tail residues, as well as recruit transcriptional corepressors (CoR). (D) Following DNA methylation of the promoter, chromatin remodeling and compaction results in a repressive transcriptional context. Note that scenarios B, C and D are not mutually exclusive. A full colour version of this figure is available at https://doi.org/10.1530/JME-17-0189.
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Figure 3
Cycles of DNA methylation through development. Relative global DNA methylation levels at various developmental times are illustrated. Escapees for DNA methylation remodeling in the male genome are illustrated by dotted lines. Cells display two major waves of demethylation. One wave occurs in PGCs (early and late demethylation) when most methylation is cleared including imprinted regions, with the notable exception of some repeat regions and single copy loci. The genome is subsequently remethylated in a gender-specific manner. The next wave of demethylation occurs during the pre-implementation period, with timing differences for paternal and maternal DNA. Imprinting DMRs can escape this remodeling. Key time points for mice and the corresponding time points identified in humans are shown. The windows of susceptibility (wos) defined by Soubry et al. (2014) for acquirements of DNA methylation alterations are indicated. The lower section of the figure illustrates the epigenetic reprogramming of a model genomic segment including 6 CpG sites, and the escape of remodeling for an exposure-mediated gain in DNA methylation, generating an epiallele, in the male germ line. White and colored circles indicate CpG sites without and with methylation, respectively. A full colour version of this figure is available at https://doi.org/10.1530/JME-17-0189.
- © 2018 Society for Endocrinology
