DNA Methylation Reprogramming during Mammalian Development - PubMed (original) (raw)

Review

DNA Methylation Reprogramming during Mammalian Development

Yang Zeng et al. Genes (Basel). 2019.

Abstract

DNA methylation (5-methylcytosine, 5mC) is a major form of DNA modification in the mammalian genome that plays critical roles in chromatin structure and gene expression. In general, DNA methylation is stably maintained in somatic tissues. However, DNA methylation patterns and levels show dynamic changes during development. Specifically, the genome undergoes two waves of global demethylation and remethylation for the purpose of producing the next generation. The first wave occurs in the germline, initiated with the erasure of global methylation in primordial germ cells (PGCs) and completed with the establishment of sex-specific methylation patterns during later stages of germ cell development. The second wave occurs after fertilization, including the erasure of most methylation marks inherited from the gametes and the subsequent establishment of the embryonic methylation pattern. The two waves of DNA methylation reprogramming involve both distinct and shared mechanisms. In this review article, we provide an overview of the key reprogramming events, focusing on the important players in these processes, including DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) family of 5mC dioxygenases.

Keywords: DNA methylation; DNMTs; TETs; embryogenesis; germ cells.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Dynamic changes in DNA methylation during mammalian development. Schematically shown are the two waves of global DNA demethylation and remethylation in the life cycle (adapted from [6]). Primordial germ cells (PGCs) initially have high levels of DNA methylation. Global demethylation occurs during PGC expansion and migration. At later stages of germ cell development (before birth in male and after birth in female), de novo methylation results in the establishment of sex-specific germ cell methylation patterns, including methylation marks at imprinted loci. Shortly after fertilization, the methylation marks inherited from the gametes are erased again (except those at imprinted loci and some retrotransposons), with the paternal genome undergoing active demethylation and the maternal genome undergoing passive demethylation. Upon implantation, a wave of de novo methylation establishes the initial embryonic methylation pattern.

Figure 2

Figure 2

DNA methylation machinery. (A) The protein domains in DNA methyltransferases (DNMTs) and ubiquitin−like with plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1) are shown (the sizes/amino acid numbers refer to mouse proteins). The DNMT1 and DNMT3 families of proteins share conserved catalytic motifs (I–X) in the C-terminal catalytic domains (DNMT3L lacks catalytic activity because some essential motifs are missing or mutated) but have distinct N-terminal regulatory regions. PBD, proliferating cell nuclear antigen (PCNA)-binding domain; NLS, nuclear localization signal; RFTS, replication foci targeting sequence; CXXC, a cysteine-rich zinc finger domain; BAH, bromo-adjacent homology domain; (GK)n, glycine/lysine repeats; PWWP, proline-tryptophan-tryptophan-proline domain; ADD, ATRX-DNMT3-DNMT3L domain; UBL, ubiquitin-like domain; TTD, tandem Tudor domain; PHD, plant homeodomain; SRA, Su(var)3-9, Enhancer of zeste, and Trithorax (SET)- and RING-associated domain; RING, really interesting new gene domain. (B) De novo and maintenance methylation activities. The de novo methyltransferases (DNMT3A, DNMT3B, and DNMT3C), in complex with their accessory factor DNMT3L, methylate unmethylated CpG sites to establish methylation patterns. The maintenance methyltransferase DNMT1, in complex with its accessory factor UHRF1, methylates hemi-methylated CpG sites at each round of DNA replication to maintain methylation patterns.

Figure 3

Figure 3

Ten-eleven translocation (TET) proteins and relevant DNA demethylation pathways. (A) The protein domains in TET proteins (TET1, TET2 and TET3) are shown (the sizes/amino acid numbers refer to mouse proteins). Their C-terminal catalytic domains contain two characteristic sequence features, a cysteine-rich region (Cys) and a double-stranded β helix (DSBH) fold. Their N-terminal regulatory regions are less conserved, with TET1 and TET3 containing a CXXC zinc finger domain. (B) DNA demethylation pathways involving TETs. TET proteins initiate DNA demethylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can be further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5fC and 5caC can be excised by thymine DNA glycosylase (TDG). The residual abasic site can then be repaired by the base excision repair (BER) pathway to complete ‘active’ demethylation. 5mC, 5hmC, 5fC, and 5caC can also be removed through DNA replication-coupled ‘passive’ dilution.

Figure 4

Figure 4

DNA demethylation in primordial germ cells (PGCs). PGCs undergo DNA demethylation in two phases. The first phase is mainly a passive process due to repression of important components of the DNA methylation machinery, resulting in global demethylation. The second phase, which affects specific loci including imprinted genes, is initiated by TET1- and TET2-mediated 5mC oxidation, followed by passive dilution of oxidized derivatives.

Figure 5

Figure 5

DNA demethylation and remethylation during early embryogenesis. Shortly after fertilization, TET3-mediated 5mC oxidation occurs in the paternal genome and the oxidized derivatives are subsequently removed through passive dilution during preimplantation development. The maternal genome mainly undergoes passive demethylation during preimplantation development. Upon implantation, a wave of de novo methylation establishes the embryonic methylation pattern.

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