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Cells Jul 2023In this review, advances in the understanding of epigenetic reprogramming from fertilization to the development of primordial germline cells in a mouse and embryo are... (Review)
Review
In this review, advances in the understanding of epigenetic reprogramming from fertilization to the development of primordial germline cells in a mouse and embryo are discussed. To gain insights into the molecular underpinnings of various diseases, it is essential to comprehend the intricate interplay between genetic, epigenetic, and environmental factors during cellular reprogramming and embryonic differentiation. An increasing range of diseases, including cancer and developmental disorders, have been linked to alterations in DNA methylation and histone modifications. Global epigenetic reprogramming occurs in mammals at two stages: post-fertilization and during the development of primordial germ cells (PGC). Epigenetic reprogramming after fertilization involves rapid demethylation of the paternal genome mediated through active and passive DNA demethylation, and gradual demethylation in the maternal genome through passive DNA demethylation. The de novo DNA methyltransferase enzymes, and , restore DNA methylation beginning from the blastocyst stage until the formation of the gastrula, and DNA maintenance methyltransferase, , maintains methylation in the somatic cells. The PGC undergo a second round of global demethylation after allocation during the formative pluripotent stage before gastrulation, where the imprints and the methylation marks on the transposable elements known as retrotransposons, including long interspersed nuclear elements (LINE-1) and intracisternal A-particle (IAP) elements are demethylated as well. Finally, DNA methylation is restored in the PGC at the implantation stage including sex-specific imprints corresponding to the sex of the embryo. This review introduces a novel perspective by uncovering how toxicants and stress stimuli impact the critical period of allocation during formative pluripotency, potentially influencing both the quantity and quality of PGCs. Furthermore, the comprehensive comparison of epigenetic events between and breaks new ground, empowering researchers to make informed decisions regarding the suitability of mouse models for their experiments.
Topics: Male; Female; Humans; Mice; Animals; Epigenesis, Genetic; Cell Differentiation; Germ Cells; Fertilization; DNA; Mammals
PubMed: 37508536
DOI: 10.3390/cells12141874 -
Nature Oct 2013DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized,... (Review)
Review
DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.
Topics: 5-Methylcytosine; Animals; Blastocyst; Cellular Reprogramming; Cytosine; DNA Methylation; DNA Repair; DNA Replication; Humans; Neoplasms; Oxidation-Reduction; Thymine DNA Glycosylase
PubMed: 24153300
DOI: 10.1038/nature12750 -
Protein & Cell Nov 2014The active DNA demethylation in early embryos is essential for subsequent development. Although the zygotic genome is globally demethylated, the DNA methylation of... (Review)
Review
The active DNA demethylation in early embryos is essential for subsequent development. Although the zygotic genome is globally demethylated, the DNA methylation of imprinted regions, part of repeat sequences and some gamete-specific regions are maintained. Recent evidence has shown that multiple proteins and biological pathways participate in the regulation of active DNA demethylation, such as TET proteins, DNA repair pathways and DNA methyltransferases. Here we review the recent understanding regarding proteins associated with active DNA demethylation and the regulatory networks controlling the active DNA demethylation in early embryos.
Topics: Animals; DNA Methylation; Embryo, Mammalian; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Genome; Humans; Mice; Models, Genetic; Zygote
PubMed: 25152302
DOI: 10.1007/s13238-014-0095-3 -
Cell Cycle (Georgetown, Tex.) May 2009DNA cytosine methylation represents an intrinsic modification signal of the genome that plays important roles in heritable gene silencing, heterochromatin formation and... (Review)
Review
DNA cytosine methylation represents an intrinsic modification signal of the genome that plays important roles in heritable gene silencing, heterochromatin formation and certain transgenerational epigenetic inheritance. In contrast to the process of DNA methylation that is catalyzed by specific classes of methyltransferases, molecular players underlying active DNA demethylation have long been elusive. Emerging biochemical and functional evidence suggests that active DNA demethylation in vertebrates can be mediated through DNA excision repair enzymes, similar to the well-known repair-based DNA demethylation mechanism in Arabidopsis. As key regulators, non-enzymatic Gadd45 proteins function to recruit enzymatic machineries and promote coupling of deamination, base and nucleotide-excision repair in the process of DNA demethylation. In this article, we review recent findings and discuss functional and evolutionary implications of such mechanisms underlying active DNA demethylation.
Topics: Animals; CpG Islands; DNA; DNA Methylation; DNA Repair; Genome; Humans; Intracellular Signaling Peptides and Proteins; GADD45 Proteins
PubMed: 19377292
DOI: 10.4161/cc.8.10.8500 -
Genes & Development Jun 2018Changes in DNA methylation are among the best-documented epigenetic alterations accompanying organismal aging. However, whether and how altered DNA methylation is...
Changes in DNA methylation are among the best-documented epigenetic alterations accompanying organismal aging. However, whether and how altered DNA methylation is causally involved in aging have remained elusive. GADD45α (growth arrest and DNA damage protein 45A) and ING1 (inhibitor of growth family member 1) are adapter proteins for site-specific demethylation by TET (ten-eleven translocation) methylcytosine dioxygenases. Here we show that double-knockout mice display segmental progeria and phenocopy impaired energy homeostasis and lipodystrophy characteristic of () mutants. Correspondingly, GADD45α occupies C/EBPβ/δ-dependent superenhancers and, cooperatively with ING1, promotes local DNA demethylation via long-range chromatin loops to permit C/EBPβ recruitment. The results indicate that enhancer methylation can affect aging and imply that C/EBP proteins play an unexpected role in this process. Our study suggests a causal nexus between DNA demethylation, metabolism, and organismal aging.
Topics: Aging; Aging, Premature; Animals; CCAAT-Enhancer-Binding Proteins; Cell Cycle Proteins; Cells, Cultured; DNA Demethylation; Homeostasis; Inhibitor of Growth Protein 1; Lipodystrophy; Mice; Mice, Knockout; Nuclear Proteins
PubMed: 29884649
DOI: 10.1101/gad.311969.118 -
Nature Communications Jan 2022DNA methylation is an epigenetic mechanism that plays important roles in gene regulation and transposon silencing. Active DNA demethylation has evolved to counterbalance...
DNA methylation is an epigenetic mechanism that plays important roles in gene regulation and transposon silencing. Active DNA demethylation has evolved to counterbalance DNA methylation at many endogenous loci. Here, we report that active DNA demethylation also targets viral DNAs, tomato yellow leaf curl China virus (TYLCCNV) and its satellite tomato yellow leaf curl China betasatellite (TYLCCNB), to promote their virulence. We demonstrate that the βC1 protein, encoded by TYLCCNB, interacts with a ROS1-like DNA glycosylase in Nicotiana benthamiana and with the DEMETER (DME) DNA glycosylase in Arabidopsis thaliana. The interaction between βC1 and DME facilitates the DNA glycosylase activity to decrease viral DNA methylation and promote viral virulence. These findings reveal that active DNA demethylation can be regulated by a viral protein to subvert DNA methylation-mediated defense.
Topics: Arabidopsis; Begomovirus; DNA Glycosylases; DNA Methylation; DNA, Viral; Host-Pathogen Interactions; Plant Diseases; Plant Proteins; Protein Binding; Satellite Viruses; Nicotiana; Viral Proteins; Virulence
PubMed: 35102164
DOI: 10.1038/s41467-022-28262-3 -
Cell Reports Dec 2021Regulatory T (T) cells play crucial roles in suppressing deleterious immune response. Here, we investigate how T cells are mechanistically induced in vitro (iT) and...
Regulatory T (T) cells play crucial roles in suppressing deleterious immune response. Here, we investigate how T cells are mechanistically induced in vitro (iT) and stabilized via transcriptional regulation of T lineage-specifying factor Foxp3. We find that acetylation of histone tails at the Foxp3 promoter is required for inducing Foxp3 transcription. Upon induction, histone acetylation signals via bromodomain-containing proteins, particularly targets of inhibitor JQ1, and sustains Foxp3 transcription via a global or trans effect. Subsequently, Tet-mediated DNA demethylation of Foxp3 cis-regulatory elements, mainly enhancer CNS2, increases chromatin accessibility and protein binding, stabilizing Foxp3 transcription and obviating the need for the histone acetylation signal. These processes transform stochastic iT induction into a stable cell fate, with the former sensitive and the latter resistant to genetic and environmental perturbations. Thus, sequential histone acetylation and DNA demethylation in Foxp3 induction and maintenance reflect stepwise mechanical switches governing iT cell lineage specification.
Topics: Acetylation; Animals; Cell Differentiation; DNA Demethylation; DNA Methylation; DNA-Binding Proteins; Female; Forkhead Transcription Factors; Gene Expression Regulation; Histones; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Promoter Regions, Genetic; Proto-Oncogene Proteins; Regulatory Sequences, Nucleic Acid; T-Lymphocytes, Regulatory
PubMed: 34910919
DOI: 10.1016/j.celrep.2021.110124 -
Annual Review of Biochemistry 2014The importance of eukaryotic DNA methylation [5-methylcytosine (5mC)] in transcriptional regulation and development was first suggested almost 40 years ago. However, the... (Review)
Review
The importance of eukaryotic DNA methylation [5-methylcytosine (5mC)] in transcriptional regulation and development was first suggested almost 40 years ago. However, the molecular mechanism underlying the dynamic nature of this epigenetic mark was not understood until recently, following the discovery that the TET proteins, a family of AlkB-like Fe(II)/α-ketoglutarate-dependent dioxygenases, can oxidize 5mC to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Since then, several mechanisms that are responsible for processing oxidized 5mC derivatives to achieve DNA demethylation have emerged. Our biochemical understanding of the DNA demethylation process has prompted new investigations into the biological functions of DNA demethylation. Characterization of two additional AlkB family proteins, FTO and ALKBH5, showed that they possess demethylase activity toward N(6)-methyladenosine (m(6)A) in RNA, indicating that members of this subfamily of dioxygenases have a general function in demethylating nucleic acids. In this review, we discuss recent advances in this emerging field, focusing on the mechanism and function of TET-mediated DNA demethylation.
Topics: 5-Methylcytosine; Animals; Cytosine; DNA; DNA Methylation; Escherichia coli; Gene Expression Regulation; Genome; Germ Cells; HEK293 Cells; Humans; Methylation; Mice; Neoplasms; Oxygen; RNA; Stem Cells; Transcriptome
PubMed: 24905787
DOI: 10.1146/annurev-biochem-060713-035513 -
Genes & Development Oct 2010The presence of 5-methylcytosine (5-mC) in DNA is a vital epigenetic mark in vertebrates. While the enzymes responsible for methylating DNA in vertebrates have been... (Review)
Review
The presence of 5-methylcytosine (5-mC) in DNA is a vital epigenetic mark in vertebrates. While the enzymes responsible for methylating DNA in vertebrates have been identified, the means by which this mark can be removed are still unclear. Recently, it has been shown that activation-induced cytidine deaminase (AID) contributes to the demethylation of DNA in certain systems. This enzyme has been intensely studied in its role as a key driver of antibody diversification in B cells, but recent observations from early development in zebrafish and mice as well as heterokaryons point to a role beyond immunology. This review takes stock of the reports linking AID and related deaminases to DNA demethylation, and describes the many important questions left to be answered in this field.
Topics: Animals; Cytidine Deaminase; DNA Methylation; Epigenesis, Genetic; Humans
PubMed: 20889711
DOI: 10.1101/gad.1963010 -
Frontiers in Oncology 2023The AlkB family (ALKBH1-8 and FTO), a member of the Fe (II)- and α-ketoglutarate-dependent dioxygenase superfamily, has shown the ability to catalyze the demethylation... (Review)
Review
The AlkB family (ALKBH1-8 and FTO), a member of the Fe (II)- and α-ketoglutarate-dependent dioxygenase superfamily, has shown the ability to catalyze the demethylation of a variety of substrates, including DNA, RNA, and histones. Methylation is one of the natural organisms' most prevalent forms of epigenetic modifications. Methylation and demethylation processes on genetic material regulate gene transcription and expression. A wide variety of enzymes are involved in these processes. The methylation levels of DNA, RNA, and histones are highly conserved. Stable methylation levels at different stages can coordinate the regulation of gene expression, DNA repair, and DNA replication. Dynamic methylation changes are essential for the abilities of cell growth, differentiation, and division. In some malignancies, the methylation of DNA, RNA, and histones is frequently altered. To date, nine AlkB homologs as demethylases have been identified in numerous cancers' biological processes. In this review, we summarize the latest advances in the research of the structures, enzymatic activities, and substrates of the AlkB homologs and the role of these nine homologs as demethylases in cancer genesis, progression, metastasis, and invasion. We provide some new directions for the AlkB homologs in cancer research. In addition, the AlkB family is expected to be a new target for tumor diagnosis and treatment.
PubMed: 37007161
DOI: 10.3389/fonc.2023.1153463