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.
Highlights
Cytosine residues are methylated at levels between 3.5 and 4.5% in adult tissues depending on the cell type; lower levels are observed in embryonic cell lines and rapidly-dividing cells [1,2]
At CpG sites, the methylation information is present in both DNA strands, meaning that after DNA replication, it can be recovered by a maintenance DNA methyltransferase with high preference for hemimethylated CpG sites, as proposed in the original maintenance DNA methylation model [9]
The dynamic nature of DNA methylation patterns has recently been illustrated by showing that the combined knock-out of all ten eleven translocation enzymes (TETs) enzymes leads to hypermethylation of bivalent promoters in human embryonic stem cells (ESC), which was dependent on DNMT3B binding to these sites [21]
Summary
Cytosine residues are methylated at levels between 3.5 and 4.5% in adult tissues depending on the cell type; lower levels are observed in embryonic cell lines and rapidly-dividing cells [1,2]. We will not present the details of DNA methylation recognition and processes involved in DNA demethylation In these fields, the reader is referred to excellent alternative reviews published recently [17,18,19]. The DNMT3A and DNMT3B enzymes do not show preference for hemimethylated target sites, and they are involved in the de novo generation of DNA methylation patterns during germ cell development and the early embryonic phase. The dynamic nature of DNA methylation patterns has recently been illustrated by showing that the combined knock-out of all TET enzymes leads to hypermethylation of bivalent promoters in human embryonic stem cells (ESC), which was dependent on DNMT3B binding to these sites [21]. For simulation of local site-specific methylation levels, these models have to be expanded, including the local targeting and preferences of DNMTs and TETs, binding of other proteins, and regulation of DNMTs and TETs, which would usher in a new era of quantitative epigenomics system biology
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