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Review
. 2018 Nov 21;9(11):566.
doi: 10.3390/genes9110566.

Molecular Processes Connecting DNA Methylation Patterns with DNA Methyltransferases and Histone Modifications in Mammalian Genomes

Albert Jeltsch  1 , Julian Broche  2 , Pavel Bashtrykov  3
Affiliations
Review

Molecular Processes Connecting DNA Methylation Patterns with DNA Methyltransferases and Histone Modifications in Mammalian Genomes

Albert Jeltsch et al. Genes (Basel). .

Erratum in

Abstract

DNA methylation is an essential part of the epigenome chromatin modification network, which also comprises several covalent histone protein post-translational modifications. All these modifications are highly interconnected, because the writers and erasers of one mark, DNA methyltransferases (DNMTs) and ten eleven translocation enzymes (TETs) in the case of DNA methylation, are directly or indirectly targeted and regulated by other marks. Here, we have collected information about the genomic distribution and variability of DNA methylation in human and mouse DNA in different genomic elements. After summarizing the impact of DNA methylation on genome evolution including CpG depletion, we describe the connection of DNA methylation with several important histone post-translational modifications, including methylation of H3K4, H3K9, H3K27, and H3K36, but also with nucleosome remodeling. Moreover, we present the mechanistic features of mammalian DNA methyltransferases and their associated factors that mediate the crosstalk between DNA methylation and chromatin modifications. Finally, we describe recent advances regarding the methylation of non-CpG sites, methylation of adenine residues in human cells and methylation of mitochondrial DNA. At several places, we highlight controversial findings or open questions demanding future experimental work.

Keywords: DNA methylation; DNA methyltransferase; histone modification; molecular epigenetics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cycle of DNA methylation and domain structure of DNMTs. (A) Cycle of DNA methylation in human cells (adapted from [9]). DNA methylation patterns are generated by de novo methyltransferases and kept through DNA replication by maintenance methylation. DNA methylation can be lost through passive or active demethylation (abbreviations: TET, ten eleven translocation enzyme; TDG, thymine-DNA glycosylase). (B) Domain structure of the mammalian DNMTs DNMT1, DNMT3A, and DNMT3B. DNMT3L is a catalytically-inactive member of the DNMT3 family, which has regulatory roles [15]. The human DNMT1, DNMT3A, DNMT3B, and DNMT3L proteins consist of 1616, 912, 853, and 387 amino acid residues, respectively. Abbreviations used: DMAPD, DNA methyltransferase-associated protein 1 interacting domain; PBD, PCNA binding domain; NLS, nuclear localization signal; RFTD, replication foci targeting domain; CXXC, CXXC domain; BAH1 and BAH2, bromo-adjacent homology domains 1 and 2; GKn, glycine lysine repeats; PWWP, PWWP domain; ADD, ATRX-DNMT3-DNMT3L domain (reprinted from [15] with permission).
Figure 2
Figure 2
Depletion of CpG dinucleotides in defined genomic elements tabulated for human chromosome 1 [29]. Abbreviations used: CpGexp, expected number of CpG sites (based on the nucleotide composition); CpGobs, observed number of CpG sites.
Figure 3
Figure 3
Exemplary DNA methylation levels in mouse hematopoietic stem cells in various genome regions (data taken from [11]). CGI: CpG islands, UTR: untranscribed region, SINE: Short Interspersed Nuclear Elements, LINE: Long Interspersed Nuclear Elements, LTR: Long Terminal Repeat
Figure 4
Figure 4
Compilation of DNA methylation density with the density of other chromatin marks in annotated CGIs in HEK293 cells (see Supplementary Text 1 for the data sources).
Figure 5
Figure 5
Compilation of DNA methylation density and the density of other chromatin marks in gene bodies in HEK293 cells (see Supplementary Text 1 for the data sources).
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