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DNA Methylation Reprogramming During Mammalian Development

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G C A T T A C G G C A T genes Review DNA Methylation Reprogramming during Mammalian Development Yang Zeng 1,2,3 and Taiping Chen 1,2,3,* 1 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA; [email protected] 2 Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA 3 Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA * Correspondence: [email protected]; Tel.: +1-512-237-9479; Fax: +1-512-237-2475 Received: 6 March 2019; Accepted: 25 March 2019; Published: 29 March 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; embryogenesis; germ cells; DNMTs; TETs 1. Introduction DNA Methylation—the addition of a methyl group to the 5-position of cytosine, forming 5-methylcytosine (5mC)—is a major form of DNA modification in many, but not all, eukaryotic organisms. In mammals, DNA methylation mainly occurs in the context of CpG dinucleotides, forming a symmetrical pattern on both strands. In the mouse genome, the majority (~60–80%) of CpG dinucleotides are methylated. Non-CpG (i.e., CpA, CpT, or CpC) methylation is rare except in special cell types, such as embryonic stem cells (ESCs), oocytes, and neurons [1]. 5mC distribution in the genome is bimodal. In general, repetitive sequences, such as transposons and centromeric and pericentric repeats, are heavily methylated, gene bodies of highly expressed genes are also methylated, whereas CpG islands (CGIs), i.e., 500–2000-bp GC-rich sequences that are frequently present in promoter regions, are usually devoid of methylation [2]. DNA methylation is essential for mammalian development and is involved in a variety of biological processes, including transcriptional regulation, transposon silencing, X chromosome inactivation, and genomic imprinting [3]. Aberrant DNA methylation patterns and mutations of genes encoding DNA methylation enzymes or regulators are associated with developmental disorders and cancer [4,5]. As a stable epigenetic mark that is heritable through cell division, DNA methylation is an important component of the cellular memory mechanism that maintains cell identities. However, Genes 2019, 10, 257; doi:10.3390/genes10040257 www.mdpi.com/journal/genes Genes 2019, 10, x FOR PEER REVIEW 2 of 18 imprinting [3]. Aberrant DNA methylation patterns and mutations of genes encoding DNA methylation enzymes or regulators are associated with developmental disorders and cancer [4,5]. Genes 2019, 10, 257 2 of 18 As a stable epigenetic mark that is heritable through cell division, DNA methylation is an important component of the cellular memory mechanism that maintains cell identities. However, the theepigenome, epigenome, including including DNA DNA methylation, methylation, needs needs to tobe be reprogrammed reprogrammed to to a a totipotent statestate forfor producingproducing thethe nextnext generation.generation. ThereThere areare twotwo waveswaves ofof globalglobal demethylationdemethylation andand remethylationremethylation duringduring the the mammalian mammalian life life cycle cycle (Figure (Figure1), one1), one occurring occurring during during germ germ cell development cell development and the and other the occurringother occurring during earlyduring embryogenesis early embryogenesis [6,7]. Epigenetic [6,7]. Epigenetic reprogramming reprogramming in the germline in the involves germline the erasureinvolves of the somatic erasure methylation of somatic patterns methylation in primordial patterns germin primordial cells (PGCs) germ and cells subsequent (PGCs) and establishment subsequent ofestablishment sex-specific germof sex-specific cell methylation germ patterns,cell methylation including patterns, methylation including marks methylation in imprinting marks control in regionsimprinting (ICRs). control Epigenetic regions reprogramming(ICRs). Epigenetic in earlyreprogramming embryos involves in early erasureembryos of involves most methylation erasure of marksmost methylation inherited from marks the inherited gametes from (exceptions the gametes include (exceptions methylation include marksmethylation in ICRs marks and in some ICRs retrotransponsons)and some retrotransponsons) at preimplantation at preimplantation stages and reestablishment stages and of reestablishment global DNA methylation of global patterns DNA uponmethylation implantation. patterns In upon this review,implantation. we discuss In this the review, highly we dynamic discuss andthe highly regulated dynamic processes and regulated of DNA demethylationprocesses of DNA and remethylation, demethylation focusing and remethylation, on the important focusing enzymes on and the regulators important that enzymes are involved and inregulators these reprogramming that are involved events. in these reprogramming events. Figure 1. Dynamic changes in DNA methylation during mammalian development. Schematically shownFigure are1. Dynamic the two waves changes of global in DNA DNA methylation demethylation during and mammalian remethylation development. in the life cycle Schematically (adapted fromshown [6 ]).are Primordialthe two waves germ of global cells (PGCs) DNA demethylat initially haveion and high remethylation levels of DNA in methylation.the life cycle (adapted Global demethylationfrom [6]). Primordial occurs during germ PGCcells expansion(PGCs) initially and migration. have high At laterlevels stages of DNA of germ methylation. cell development Global (beforedemethylation birth in occurs male and during after PGC birth expansion in female), and de migrat novoion. methylation At later stages results of in germ the establishmentcell development of sex-specific(before birth germ in male cell methylationand after birth patterns, in female), including de novo methylation methylation marks results at imprintedin the establishment loci. Shortly of aftersex-specific fertilization, germ the cell methylation methylation marks patterns, inherited includ froming methylation the gametes aremarks erased at imprinted again (except loci. those Shortly at imprintedafter fertilization, loci and the some methylatio retrotransposons),n marks inherited with the paternalfrom the genomegametes undergoing are erased again active (except demethylation those at andimprinted the maternal loci genomeand some undergoing retrotransposons), passive demethylation. with the paternal Upon implantation, genome undergoing a wave of de active novo methylationdemethylation establishes and the thematernal initial embryonicgenome undergoing methylation passive pattern. demethylation. Upon implantation, a wave of de novo methylation establishes the initial embryonic methylation pattern. 2. DNA Methyltransferases and Regulators 2. DNAAs CpG/CpG Methyltransferases dyads are symmetrical,and Regulators Holliday and Pugh, and Riggs independently proposed that methylatedAs CpG/CpG CpG sites dyads could are be symmetrical, heritable through Holliday semi-conservative and Pugh, and DNA Riggs replication independently [8,9]. The proposed theory wouldthat methylated predict at leastCpG twosites catalytic could be activities—de heritable through novo semi-conservative methylation activity DNA for thereplication establishment [8,9]. The of methylationtheory would patterns predict and at maintenance least two methylationcatalytic activities—de activity for converting novo methylation hemi-methylated activity CpG for sites the toestablishment fully methylated of methylation ones during patterns DNA replication. and maintenance Subsequent methylation work identified activity DNA for methyltransferases converting hemi- (DNMTs)methylated with CpG distinct sites to properties fully methylated and their ones accessory during DNA factors, replication. including Subs ubiquitinequent− likework with identified plant homeodomainDNA methyltransferases (PHD) and (DNMTs) really interesting with distinct new pr geneoperties (RING) and fingertheir accessory domains factors, 1 (UHRF1) including and DNMT3Lubiquitin− [10like]. with plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1) and DNMT3L [10]. Genes 2019, 10, 257 3 of 18 2.1. DNMT1 and UHRF1—Key Components of Maintenance Methylation Machinery
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