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![Cycle of DNA methylation and domain structure of DNMTs. (A) Cycle of DNA methylation in human cells (adapted from [9]). DNA methylation patterns are generated by de novo methyltransferases and kept through DNA replication by maintenance methylation. DNA methylation can be lost through passive or active demethylation (abbreviations: TET, ten eleven translocation enzyme; TDG, thymine-DNA glycosylase). (B) Domain structure of the mammalian DNMTs DNMT1, DNMT3A, and DNMT3B. DNMT3L is a catalytically-inactive member of the DNMT3 family, which has regulatory roles [15]. The human DNMT1, DNMT3A, DNMT3B, and DNMT3L proteins consist of 1616, 912, 853, and 387 amino acid residues, respectively. Abbreviations used: DMAPD, DNA methyltransferase-associated protein 1 interacting domain; PBD, PCNA binding domain; NLS, nuclear localization signal; RFTD, replication foci targeting domain; CXXC, CXXC domain; BAH1 and BAH2, bromo-adjacent homology domains 1 and 2; GK n , glycine lysine repeats; PWWP, PWWP domain; ADD, ATRX-DNMT3-DNMT3L domain (reprinted from [15] with permission).](publication/329134340/figure/fig1/AS:695955296890880@1542940081609/Cycle-of-DNA-methylation-and-domain-structure-of-DNMTs-A-Cycle-of-DNA-methylation-in.png)
Cycle of DNA methylation and domain structure of DNMTs. (A) Cycle of DNA methylation in human cells (adapted from [9]). DNA methylation patterns are generated by de novo methyltransferases and kept through DNA replication by maintenance methylation. DNA methylation can be lost through passive or active demethylation (abbreviations: TET, ten eleven translocation enzyme; TDG, thymine-DNA glycosylase). (B) Domain structure of the mammalian DNMTs DNMT1, DNMT3A, and DNMT3B. DNMT3L is a catalytically-inactive member of the DNMT3 family, which has regulatory roles [15]. The human DNMT1, DNMT3A, DNMT3B, and DNMT3L proteins consist of 1616, 912, 853, and 387 amino acid residues, respectively. Abbreviations used: DMAPD, DNA methyltransferase-associated protein 1 interacting domain; PBD, PCNA binding domain; NLS, nuclear localization signal; RFTD, replication foci targeting domain; CXXC, CXXC domain; BAH1 and BAH2, bromo-adjacent homology domains 1 and 2; GK n , glycine lysine repeats; PWWP, PWWP domain; ADD, ATRX-DNMT3-DNMT3L domain (reprinted from [15] with permission).
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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 th...
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Context 1
... methylation mainly occurs at palindromic CpG sites (28 million sites in the case of the diploid human genome), which are methylated to 70-80%, but cytosines in non-CpG sites are methylated, as well (see below). 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] ( Figure 1A). Here, we describe DNA methylation patterns in human and mouse DNA in the context of their evolution and compiled information on their correlation with important histone post-translational modifications. ...
Context 2
... contrast, 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. All mammalian DNMTs contain a C-terminal catalytic domain, which has structural and sequence homology to prokaryotic DNA-(cytosine C5)-methyltransferases and a larger N-terminal part with different domains involved in targeting and regulation ( Figure 1B). DNA demethylation is initiated by the action of the TET family dioxygenases, which catalyze the oxidation of methylcytosine [19]. ...
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Epigenetic inheritance refers to the faithful replication of DNA methylation and histone modification independent of DNA sequence. Nucleosomes block access to DNA methyltransferases, unless they are remodeled by DECREASE IN DNA METHYLATION1 (DDM1 Lsh/HELLS ), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 activity results...
Citations
... A series of methylated Lys residues associated with the epigenetic mechanisms have been reported in nucleosomal histones, such as mono (me1), di (me2), and tri (me3)-methylation of Lys residues at positions 4,9,27,36, and 79 of histone H3 (H3K4, H3K9, H3K27, H3K36, and H3K79); at positions 20 and 59 of histone H4 (H4K20 and H4K59); and at position 26 of histone H1B [2,7]. The methyl groups are transferred from S-adenosyl methionine (SAM) to the ε-amino group of Lys, and the biochemical reactions are catalyzed by a group of enzymes, collectively termed histone Lys methyltransferase (HKMT) [8]. ...
... However, the biological role of each HKMT remains elusive [2,7]. In general, H3K4me3, H3K79me2, and H4K20me1 are involved in transcriptional activation, whereas H3K9me2, H3K9me3, and H3K27me3 are associated with gene silencing [2,9]. ...
Epigenetic writers including DNA and histone lysine methyltransferases (DNMT and HKMT, respectively) play an initiative role in the differentiation and development of eukaryotic organisms through the spatiotemporal regulation of functional gene expressions. However, the epigenetic mechanisms have long been suspected in helminth parasites lacking the major DNA methyltransferases DNMT1 and DNMT3a/3b. Very little information on the evolutionary status of the epigenetic tools and their role in regulating chromosomal genes is currently available in the parasitic trematodes. We previously suggested the probable role of a DNMT2-like protein (CsDNMT2) as a genuine epigenetic writer in a trematode parasite Clonorchis sinensis. Here, we analyzed the phylogeny of HKMT subfamily members in the liver fluke and other platyhelminth species. The platyhelminth genomes examined conserved genes for the most of SET domain-containing HKMT and Disruptor of Telomeric Silencing 1 subfamilies, while some genes were expanded specifically in certain platyhelminth genomes. Related to the high gene dosages for HKMT activities covering differential but somewhat overlapping substrate specificities, variously methylated histones were recognized throughout the tissues/organs of C. sinensis adults. The temporal expressions of genes involved in eggshell formation were gradually decreased to their lowest levels proportionally to aging, whereas those of some epigenetic tool genes were re-boosted in the later adult stages of the parasite. Furthermore, these expression levels were significantly affected by treatment with DNMT and HKMT inhibitors. Our data strongly suggest that methylated histones are potent epigenetic markers that modulate the spatiotemporal expressions of C. sinensis genes, especially those involved in sexual reproduction.
... The output files were processed using Microsoft Excel (Professional Plus 2019). DNA methylation at non-CpG sites is known to be much lower in human cell lines and it was not investigated in this paper [32]. ...
DNA methylation is critically involved in the regulation of chromatin states and cell-type-specific gene expression. The exclusive expression of imprinted genes from either the maternal or the paternal allele is regulated by allele-specific DNA methylation at imprinting control regions (ICRs). Aberrant DNA hyper- or hypomethylation at the ICR1 of the H19/IGF2 imprinting locus is characteristic for the imprinting disorders Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS), respectively. In this paper, we performed epigenome editing to induce targeted DNA demethylation at ICR1 in HEK293 cells using dCas9-SunTag and the catalytic domain of TET1. 5-methylcytosine (5mC) levels at the target locus were reduced up to 90% and, 27 days after transient transfection, >60% demethylation was still observed. Consistent with the stable demethylation of CTCF-binding sites within the ICR1, the occupancy of the DNA methylation-sensitive insulator CTCF protein increased by >2-fold throughout the 27 days. Additionally, the H19 expression was increased by 2-fold stably, while IGF2 was repressed though only transiently. Our data illustrate the ability of epigenome editing to implement long-term changes in DNA methylation at imprinting control regions after a single transient treatment, potentially paving the way for therapeutic epigenome editing approaches in the treatment of imprinting disorders.
... On the contrary, demethylation of 5 mC is driven by the TET family of dioxygenases that oxidize 5 mC to form 5-hydroxymethylcytosine ( 5 hmC) which can be further oxidized to form carbonylmethylcytosine (camC) and formylmethylcytosine (fmC), or glycosylated (28). The activity and expression levels of cytosine methyltransferases are also affected by specific epigenetic marks and post-translational modifications such as the histone methylation H3K4, H3K36 (29), highlighting the complexity of the epigenetic network. ...
Epigenetic modifications are chemical modifications that affect gene expression without altering DNA sequences. In particular, epigenetic chemical modifications can occur on histone proteins -mainly acetylation, methylation-, and on DNA and RNA molecules -mainly methylation-. Additional mechanisms, such as RNA-mediated regulation of gene expression and determinants of the genomic architecture can also affect gene expression. Importantly, depending on the cellular context and environment, epigenetic processes can drive developmental programs as well as functional plasticity. However, misbalanced epigenetic regulation can result in disease, particularly in the context of metabolic diseases, cancer, and ageing. Non-communicable chronic diseases (NCCD) and ageing share common features including altered metabolism, systemic meta-inflammation, dysfunctional immune system responses, and oxidative stress, among others. In this scenario, unbalanced diets, such as high sugar and high saturated fatty acids consumption, together with sedentary habits, are risk factors implicated in the development of NCCD and premature ageing. The nutritional and metabolic status of individuals interact with epigenetics at different levels. Thus, it is crucial to understand how we can modulate epigenetic marks through both lifestyle habits and targeted clinical interventions -including fasting mimicking diets, nutraceuticals, and bioactive compounds- which will contribute to restore the metabolic homeostasis in NCCD. Here, we first describe key metabolites from cellular metabolic pathways used as substrates to “write” the epigenetic marks; and cofactors that modulate the activity of the epigenetic enzymes; then, we briefly show how metabolic and epigenetic imbalances may result in disease; and, finally, we show several examples of nutritional interventions - diet based interventions, bioactive compounds, and nutraceuticals- and exercise to counteract epigenetic alterations.
... The pathobiology of OM included mechanisms of oxidative stress, inflammation, and vitamin D metabolism [12,18], and in the present study, our investigation aimed to determine whether the DNMT genes involved in the metabolism of the methyl groups are related to this inflammatory condition. DNA methylation is one of the epigenetic markers that orchestrate gene expression so changes in the expression or activity of enzymes that catalyze DNA methylation can impact gene expression, which, in turn, can contribute to disease development [1,2,4]. ...
... Mucosal regeneration includes cell proliferation and differentiation, which are regulated by DNA methylation. This can alter the expression of a variety of genes [2]. ...
... In fact, little is known about all the functions of each of the DNMTs, which go beyond providing DNA methylation. In addition, sites other than CpGs can be methylated, especially by DNMT3, indicating that the role of this family of enzymes is quite complex [1,2]. MTX ® , on the other hand, is known for its nephrotoxicity, and although an increase in creatinine levels in pediatric patients with hematologic malignancies after treatment with chemotherapy is expected, data from the children in the present study are within the normal range for this condition (0.4 to 1.3 mg/dL) [43]. ...
The aim of this study was to investigate the association of single-nucleotide polymorphisms (SNPs) and the DNA methylation profiles of the DNA methyltransferase (DNMT) gene family with oral mucositis in children and adolescents with hematologic malignancies treated with methotrexate (MTX®). The population was comprised of healthy and oncopediatric patients aged between 4 and 19 years. An evaluation of oral conditions was performed using the Oral Assessment Guide. Demographic, clinical, hematological, and biochemical data were obtained from medical records. Genomic DNA extracted from oral mucosal cells was used for the analysis of polymorphisms in DNMT1 (rs2228611), DNMT3A (rs7590760), and DNMT3B (rs6087990) using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique (n = 102) and for DNA methylation using the methylation-specific PCR (MSP) technique (n = 85). The allele and genotypic frequencies of SNPs did not reveal any differences between patients with or without oral mucositis. An increase in the methylation frequency for DNMT1 in patients recovered from mucositis was detected. The DNMT3A methylated profile associated with the CC genotype (SNP rs7590760) appeared to be connected to higher values of creatinine. In addition, the DNMT3B unmethylated profile associated with the CC genotype (SNP rs6087990) appeared to be connected with higher values of creatinine. We conclude that the DNMT1 methylation profile is associated with the post-mucositis period and that the genetic and epigenetic profiles of DNMT3A and DNMT3B are associated with creatinine levels.
... Except for the direct effects on the chemical and physical properties of DNA and histones, PTMs and DNA methylation also change the recruitment of remodeling complexes in an indirect way and further affect the nucleosome dynamics together. The PTMs, including the methylation of histone H3 lysine 4 (H3K4), histone H3 lysine 9 (H3K9), histone H3 lysine 27 (H3K27), and histone H3 lysine 36 (H3K36), have a close connection with DNA methylation [137]. In the case of histone H3 lysine 4 (H3K4), the methylation effect of DNA methyltransferase 3 Like (DNMT3L) could be strongly inhibited by the methylation at histone H3 lysine 4 (H3K4), but it was insensitive to modifications at other positions [138]. ...
The nucleosome, which organizes the long coil of genomic DNA in a highly condensed, polymeric way, is thought to be the basic unit of chromosomal structure. As the most important protein–DNA complex, its structural and dynamic features have been successively revealed in recent years. However, its regulatory mechanism, which is modulated by multiple factors, still requires systemic discussion. This study summarizes the regulatory factors of the nucleosome’s dynamic features from the perspective of histone modification, DNA methylation, and the nucleosome-interacting factors (transcription factors and nucleosome-remodeling proteins and cations) and focuses on the research exploring the molecular mechanism through both computational and experimental approaches. The regulatory factors that affect the dynamic features of nucleosomes are also discussed in detail, such as unwrapping, wrapping, sliding, and stacking. Due to the complexity of the high-order topological structures of nucleosomes and the comprehensive effects of regulatory factors, the research on the functional modulation mechanism of nucleosomes has encountered great challenges. The integration of computational and experimental approaches, the construction of physical modes for nucleosomes, and the application of deep learning techniques will provide promising opportunities for further exploration.
... Among the epigenetic regulators are DNA methylation/demethylation, chromatin remodeling, histone modifications and non-coding RNAs (ncRNAs) [1]. Moreover, it is increasingly clear that they do not play all alone but regulate gene expression simultaneously, combining in a wide regulatory network [2][3][4]. ...
In the last few years, more and more scientists have suggested and confirmed that epigenetic regulators are tightly connected and form a comprehensive network of regulatory pathways and feedback loops. This is particularly interesting for a better understanding of processes that occur in the development and progression of various diseases. Appearing on the preclinical stages of diseases, epigenetic aberrations may be prominent biomarkers. Being dynamic and reversible, epigenetic modifications could become targets for a novel option for therapy. Therefore, in this review, we are focusing on histone modifications and ncRNAs, their mutual regulation, role in cellular processes and potential clinical application.
... Meanwhile, propolis chemical components may target proteins engaged in the epigenetic controlling gene expression [20,21]. Regulation of various cellular processes such as developmental programs, genome integrity, gene expression and cell profilation, require the epigenetic factors to work with each other [22]. Propolis can also disrupt oncogenic pathways signals, induce apoptosis and stop cell growth [23,24]. ...
... It could be also shown that the mechanism by which compounds in propolis support health appear to be linked to its antioxidant and inflammatory activities; although in most cases the range and scope of physiological effects of this complex nutrient are wide and varied. Also, we can conclude that may be epigenetic factors, such as DNA methylation and histone modifications, work together to regulate essential cellular mechanisms such as developmental programs, genome integrity, gene expression, cell proliferation and survival and death pathways [21,22]. Further studies are clearly necessary in order to characterize propolis-derived chemical compounds as new epi-drugs. ...
Compounds presented in propolis may target proteins engaged in regulation of gene expression. Sixty males of albino rats classified into five groups were used to evaluate nephron-protective effect of propolis against gentamicin toxicity. Gene expression was used as a tool to identify the role of propolis in reducing gentamicin-side effects. The study was designed as G1: animals received only saline as a control, G2: animals given propolis orally by stomach tube (500 mg/kg b.w) for eight days, G3: animals received daily intraperitoneal injection of gentami-cin (100 mg/kg b.w) for eight days, G4: animals treated with propolis after one hour from injection by gentamicin and G5: animals treated with propolis after finishing injection by gentamicin and continued to the end of the experiment. Half of all animals were sacrificed after three weeks (1 st period) and the others after six weeks (2 nd period). Results indicated that propolis effect after one week from treatment by gentamicin was better than one hour in both of as-partate aminotransferase (AST) and alanine ami-notransferase (ALT) levels. Creatinine, urea levels and malondialdehyde (MDA) activity were significantly decreased with using propolis supplementa-tion in gentamicin-treated rats. Propolis increased significantly the level of total antioxidant capacity (TAC) in both 1 h (G4) and 1 weak (G5) but the increase in G5 was more than G4 in the two periods. Concerning gene expression analysis of inflammation related genes (tumour necrosis factor α; TNFα and nuclear factor-kappa B; NFKB), kidney regener-ation-related gene (Nephrin) and apoptosis-related gene (Caspase 3), propolis treatments showed increased expression of TNFα and NFKB which significantly down-regulated following administration of propolis for 1 h (G4) and 1 weak (G5). Treatment with propolis stimulated Nephrin gene and enhanced the expression in the first and second periods, whereas reduced the increasing expression of Caspase 3 that induced by gentamicin in the first and second periods. Practically use of propolis inhibits histopathological toxic effect of gentamicin on kidney tissue. In conclusions, propolis can reduce the side effects of gentamicin and the treatment by prop-olis as remedial effects is better than protective effects in each of enzyme assays, gene expression of TNFα, NFKB, Nephrin and Caspase 3 and histologi-cal studies.
... Meanwhile, propolis chemical components may target proteins engaged in the epigenetic controlling gene expression [20,21]. Regulation of various cellular processes such as developmental programs, genome integrity, gene expression and cell profilation, require the epigenetic factors to work with each other [22]. Propolis can also disrupt oncogenic pathways signals, induce apoptosis and stop cell growth [23,24]. ...
... It could be also shown that the mechanism by which compounds in propolis support health appear to be linked to its antioxidant and inflammatory activities; although in most cases the range and scope of physiological effects of this complex nutrient are wide and varied. Also, we can conclude that may be epigenetic factors, such as DNA methylation and histone modifications, work together to regulate essential cellular mechanisms such as developmental programs, genome integrity, gene expression, cell proliferation and survival and death pathways [21,22]. Further studies are clearly necessary in order to characterize propolis-derived chemical compounds as new epi-drugs. ...
Compounds presented in propolis may target proteins engaged in regulation of gene expression. Sixty males of albino rats classified into five groups were used to evaluate nephron-protective effect of propolis against gentamicin toxicity. Gene expression was used as a tool to identify the role of propolis in reducing gentamicin-side effects. The study was designed as G1: animals received only saline as a control, G2: animals given propolis orally by stomach tube (500 mg/kg b.w) for eight days, G3: animals received daily intraperitoneal injection of gentami-cin (100 mg/kg b.w) for eight days, G4: animals treated with propolis after one hour from injection by gentamicin and G5: animals treated with propolis after finishing injection by gentamicin and continued to the end of the experiment. Half of all animals were sacrificed after three weeks (1 st period) and the others after six weeks (2 nd period). Results indicated that propolis effect after one week from treatment by gentamicin was better than one hour in both of as-partate aminotransferase (AST) and alanine ami-notransferase (ALT) levels. Creatinine, urea levels and malondialdehyde (MDA) activity were significantly decreased with using propolis supplementa-tion in gentamicin-treated rats. Propolis increased significantly the level of total antioxidant capacity (TAC) in both 1 h (G4) and 1 weak (G5) but the increase in G5 was more than G4 in the two periods. Concerning gene expression analysis of inflammation related genes (tumour necrosis factor α; TNFα and nuclear factor-kappa B; NFKB), kidney regener-ation-related gene (Nephrin) and apoptosis-related gene (Caspase 3), propolis treatments showed increased expression of TNFα and NFKB which significantly down-regulated following administration of propolis for 1 h (G4) and 1 weak (G5). Treatment with propolis stimulated Nephrin gene and enhanced the expression in the first and second periods, whereas reduced the increasing expression of Caspase 3 that induced by gentamicin in the first and second periods. Practically use of propolis inhibits histopathological toxic effect of gentamicin on kidney tissue. In conclusions, propolis can reduce the side effects of gentamicin and the treatment by prop-olis as remedial effects is better than protective effects in each of enzyme assays, gene expression of TNFα, NFKB, Nephrin and Caspase 3 and histologi-cal studies.
... 5 In the human genome, DNA methylation occurs at about 70-80% of all CpG sites, but also at non-CpG sites. 1,[6][7] The DNA methyltransferase paralogs DNMT3A and DNMT3B 8 catalyze the methylation of cytosine residues in DNA with a preference for CpG sites [3][4] and set up DNA methylation patterns during gametogenesis and post-implantation development. 2,9 DNMT3A is essential for the development of mammals, but it also has important roles in carcinogenesis. ...
Somatic R882H DNMT3A mutations occur frequently in AML, but their pathogenic mechanism is unclear. As R882H mutations usually are heterozygous, wildtype (WT) and R882H subunits co-exist in affected cells. R882 is located in the RD interface of DNMT3A tetramers, which forms the DNA binding site. R882H causes strong changes in the flanking sequence preferences of DNMT3A. Here, we analyzed flanking sequence preferences for CGNNNN sites showing that most disfavored sites are methylated 4-5 fold slower by R882H than WT, while it methylates most preferred sites 2-fold faster. Overall, R882H was more active than WT at 13% and less active at 52% of all CGNNNN sites. We prepared mixed DNMT3A heterotetramers containing WT and R882H subunits and show that mixed complexes preferentially assemble with an R882H/R882H RD interface. Structural comparisons and MD simulations confirmed the conclusion that the R882H RD interface is more stable than that of WT, in part because H882 forms an inter-subunit contact in the RD interface, while R882 contacts the DNA. As the subunits at the RD interface form the active centers of the DNMT3A tetramer, R882H specific flanking sequence preferences of DNMT3A were observed in mixed tetrameric complexes containing WT and R882H subunits, and they are not diluted by the “averaged” effects of mixed or WT interfaces. Hence, R882H has a dominant effect on the flanking sequence preferences and other catalytic properties of DNMT3A in samples containing WT and R882H subunits, which may explain its pathogenic effect in heterozygous state.
... The best understood epigenetic modification of DNA is methylation, the focus of this article. DNA methylation (DNAm) is catalysed by the DNA methyltransferase (DNMT) enzyme family [4]. DNMT target mainly cytosine in a 5 -CG-3 context in mammals, resulting in the formation of 5-methyldeoxycytosine (5mC). ...
Cardiovascular epigenomics is a relatively young field of research, yet it is providing novel insights into gene regulation in the atherosclerotic arterial wall. That information is already pointing to new avenues for atherosclerosis (AS) prevention and therapy. In parallel, advances in nanoparticle (NP) technology allow effective targeting of drugs and bioactive molecules to the vascular wall. The partnership of NP technology and epigenetics in AS is just beginning and promises to produce novel exciting candidate treatments. Here, we briefly discuss the most relevant recent advances in the two fields. We focus on AS and DNA methylation, as the DNA methylome of that condition is better understood in comparison with the rest of the cardiovascular disease field. In particular, we review the most recent advances in NP-based delivery systems and their use for DNA methylome modification in inflammation. We also address the promises of DNA methyltransferase inhibitors for prevention and therapy. Furthermore, we emphasize the unique challenges in designing therapies that target the cardiovascular epigenome. Lastly, we touch the issue of human exposure to industrial NPs and its impact on the epigenome as a reminder of the undesired effects that any NP-based therapy must avoid to be apt for secondary prevention of AS.
