Recent Insights into the Mechanisms ofDe Novoand Maintenance of DNA Methylation in Mammals

Abstract

DNA methylation is one of the key epigenetic mechanisms essential for transcriptional regulation, silencing of transposable elements, and genome stabilization. Under physiological conditions, DNA methylation is erased and then established genome-wide during gametogenesis and embryogenesis. De novo DNA methylation by the enzymatic reaction of the de novo DNA methyltransferases (DNMTs), DNMT3A and DNMT3B, occurs during the establishment of DNA methylation patterns specific to each germ cell type or somatic cell type after the erasure. Once cell type-specific DNA methylation patterns are established during embryogenesis, which can extend to early childhood, the maintenance of DNA methyltransferase DNMT1 and its cofactor UHRF1 cooperatively maintain the pattern throughout the individual's lifetime. Recently, our group found that UHRF1 is also involved in de novo DNA methylation during oogenesis. Moreover, our group has identified two genes, CDCA7 and HELLS, to be the causative genes of ICF syndrome, characterized by hypomethylation of centromeric and pericentromeric repetitive sequences. Because CDCA7/HELLS comprise a chromatin remodeling complex, there are evidently certain regions where chromatin remodeling is required to achieve maintenance of DNA methylation. In this chapter, the current situation with respect to our understanding of de novo and maintenance of DNA methylation mechanisms under physiological conditions in mammals is summarized.

Chromatin remodeling in replication‐uncoupled maintenance DNA methylation and chromosome stability: Insights from ICF syndrome studies

“…During embryogenesis, DNA methylation patterns that are specific to each cell type are established by DNMT3A and DNMT3B. Subsequently, these patterns are maintained by the DNMT1/UHRF1 complex throughout the individual's lifetime (Unoki, 2019 ). UHRF1 (also known as Np95 and ICBP90) is a unique protein harboring a ubiquitin‐like (UBL) domain, a tandem Tudor domain (TTD), a PHD finger, a SET and RING‐associated (SRA) domain, and a RING domain.…”

“…At these regions, methylation by DNMT1 likely occurs after the wrapping of hemi‐methylated DNA around nucleosomes, because this type of maintenance exhibits much slower kinetics (up to 24 hr) than does replication‐coupled maintenance (Ming et al., 2020 ) and requires multiple mono‐ubiquitylation of histone H3 in nucleosomes by the RING domain of UHRF1 (Nishiyama et al., 2020 ), which stimulates Dnmt1 activity cooperating with the SRA domain of UHRF1 (Mishima et al., 2020 ). As chromatin acts as a barrier to DNA methylation, possibly because hemi‐methylated DNA wrapped around nucleosomes is not a suitable substrate for DNMT1 (Ming et al., 2020 ; Mishima et al., 2017 ), chromatin remodeling was expected to be required for replication‐uncoupled maintenance DNA methylation (Unoki, 2019 ). As expected, it was revealed that HELLS, which forms a chromatin remodeling complex with CDCA7 (Jenness et al., 2018 ), facilitates this type of maintenance by enhancing the chromatin association of UHRF1 (Figure 1b ) (Han et al., 2020 ; Ming et al., 2020 ).…”

“…chromatin remodeling, chromosome stability, DNA methylation, DNA repair, DNA replication, homologous recombination, ICF syndrome, multiradial chromosome, nonhomologous end joining, pericentromere UNOKI a major role in the transcriptional regulation of gene expression, silencing of transposable elements, maintenance of genome integrity, and chromosome stability, and is classified into two types (Unoki, 2019). One is de novo DNA methylation, in which methyl groups are added to cytosine residues in unmethylated DNA.…”

“…In mammals, heterochromatin is tightly associated with the di‐ and tri‐methylation of histone H3 lysine 9 (H3K9me2/me3) and of the C5 positions of cytosine in the CpG context (called DNA methylation hereafter). DNA methylation plays a major role in the transcriptional regulation of gene expression, silencing of transposable elements, maintenance of genome integrity, and chromosome stability, and is classified into two types (Unoki, 2019 ). One is de novo DNA methylation, in which methyl groups are added to cytosine residues in unmethylated DNA.…”

Radiation-induced cardiovascular disease: an overlooked role for DNA methylation?

“…The addition of a methyl group to C5 of a cytosine leads to the production of a stable covalent bond that requires a high degree of energy to be broken. An observation that led to the mistaken belief of the irreversibility of DNA methylation [ 91 , 92 ].

Figure 2.

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