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DNA methylation analysis using bisulfite sequencing data
Published in Altuna Akalin, Computational Genomics with R, 2020
DNA methylation is established by DNA methyltransferases DNMT3A and DNMT3B in combination with DNMT3L and maintained through cell division by the methyltransferase DNMT1 and associated proteins. DNMT3a and DNMT3b are in charge of the de novo methylation during early development. Loss of 5mC can be achieved passively by dilution during replication or exclusion of DNMT1 from the nucleus. Recent discoveries of the ten-eleven translocation (TET) family of proteins and their ability to convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) in vertebrates provide a path for catalyzed active DNA demethylation (Tahiliani et al., 2009). Iterative oxidations of 5hmC catalyzed by TET result in 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5caC mark is excised from DNA by G/T mismatch-specific thymine-DNA glycosylase (TDG), which as a result reverts cytosine residue to its unmodified state (He et al., 2011). Apart from these, mainly bacteria, but possibly higher eukaryotes, contain base modifications on bases other than cytosine, such as methylated adenine or guanine (Clark et al., 2011).
Intrinsic and Extrinsic Factors That Influence Epigenetics
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Ivan Nalvarte, Joëlle Rüegg, Carlos Guerrero-Bosagna
Increasing evidence points toward nuclear receptor (NR) transcription factors, including the sex hormone receptors, as having an important role in epigenetic regulation of gene expression. NRs can recruit both chromatin-remodeling co-activators with histone acetylase (HAT) and deacetylase (HDAC) activities (33,34) and direct de novo DNA methylation and de-methylation to regulatory regions (34,35). The mechanisms underlying NR-induced DNA de-methylation is still unclear, however, recent reports show evidence that at least ERα (36), ERβ (37), retinoic acid receptor alpha (RARα) (38), and androgen receptor (AR) (39) can direct DNA de-methylation to specific genomic loci by interacting with thymine DNA glycosylase (TDG). TDG belongs to the base excision repair machinery and is part of the final step in DNA de-methylation by replacing deaminated methylcytosines to unmethylated cytosines. In the case of ERα, the TDG-ERα interaction is dependent on E2 activation (36), however, for ERβ this does not seem to be the case (37). Instead, it can be speculated that antagonistic ligands may be more important in modulating the interaction between ERβ and TDG. In view of the essential roles that sex hormones play in sexual differentiation and reproduction, deregulations in sex hormone signaling may directly impose lasting effects on the epigenome, not only in the affected individual, but also in the offspring.
Epigenetics from Oocytes to Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Dagnė Daškevičiūtė, Marta Sanchez-Delgado, David Monk
In the fertilized mouse oocytes, now termed “zygote,” the two parental genomes are spatially separated within the maternal and paternal pronuclei. Even before the completion of the first cell division, the maternally and paternally derived DNA have asymmetric DNA methylation profiles, with the paternal genome having undergone active demethylation independent of replication in an enzymatic-mediated reaction performed by the ten-eleven translocation (TET) protein family.13,14 The methylation dynamics are similar in human embryos, with the notable exception that the most drastic demethylation occurs from fertilization until the two-cell stage.15,16 There are three members of the TET family: TET1, TET2 and TET3, all capable of oxidizing 5mC to intermediate states that include 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (Figure 9.2a).17 Paternal genome demethylation is carried out by TET3 which is abundantly expressed in the oocyte and present in the zygote at high levels.18–20 5fC and 5caC are committed intermediates of the oxidative demethylation process and are magnitudes less abundant than 5hmC, and unlike 5hmC, are not enriched in somatic tissues. Despite both 5fC and 5caC having the potential for active removal by thymine DNA glycosylases (TDG) through base excision repair,21 they actually show a gradual decline in the paternal pronucleus, therefore a replication-coupled demethylation model is favored, since oxidized 5mC derivatives are poorly recognized by DNMT1.22
Early-life adversity-induced long-term epigenetic programming associated with early onset of chronic physical aggression: Studies in humans and animals
Published in The World Journal of Biological Psychiatry, 2019
Dimitry A. Chistiakov, Vladimir P. Chekhonin
DNA methyltransferases (DNMTs) are involved in cytosine methylation using S-adenosyl methionine as the methyl donor. In mammals, DNMT1 is the most abundant DNA methyltransferase that plays a key role in maintenance of genome-wide methylation patterns. This enzyme is more active on hemimethylated DNA than on unmethylated CpG dinucleotides and therefore preferentially methylates hemimethylated substrates (Mohan & Chaillet 2013). In contrast, DNMT3 acts on unmethylated and hemimethylated DNA at equal rates. DNMT3a, DNMT3b and DNMT3L comprise a family of DNMT3 methylases. DNMT3a and DNMT3b are implicated in de novo DNA methylation (Okano et al. 1999). DNMT3L lacks methyltransferase activity but is essential for the establishment of maternal methylation imprints and appropriate (allele-specific) expression of maternally imprinted genes (Hata et al. 2002). DNA demethylation is performed through complex DNA excision/repair-based mechanisms involving oxidation of the methyl group by TET dioxygenases and further restoration of intact cytosines (Wu & Zhang 2014). 5-Hydroxymethylcytosine may be reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair (Kohli & Zhang 2013). However, conversion of 5-hydroxymethylcytosine to cytosine is not completely resolved so far.
The clinical values of dysregulated DNA methylation and demethylation intermediates in acute lymphoblastic leukemia
Published in Hematology, 2019
Lin-Lin Cao, Hangqi Liu, Zhihong Yue, Lin Pei, Hui Wang, Mei Jia
Despite its stability, DNA methylation can still be reversed to its unmodified state by DNA demethylation process. DNA demethylation is usually mediated by TET proteins, which oxidize 5-methylcytosine (5-mC) iteratively to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). 5-caC was further cleaved by thymine DNA glycosylase and restored to a normal cytosine by base-excision repair [8]. TET proteins require iron and α-ketoglutarate (α-KG) as co-substrates, and catalyze oxidative decarboxylation of α-KG, thereby generating an enzyme-bound Fe(IV)-oxo intermediate that converts 5mC to 5hmC, 5-fC and 5-caC [9]. The balance between DNA methylation and demethylation is frequently deregulated in cancer, leading to aberrant modification patterns. Mutations that disrupt the functions of TET genes cause changes in 5-mC and 5-hmC levels of hematopoietic stem cells and participate in the pathogenesis of hematopoietic malignancies [10,11]. However, the clinical implications of DNA methylation and its oxidation products have not been comprehensively evaluated in patients with ALL.
Epigenetic regulation of T cell development
Published in International Reviews of Immunology, 2023
Avik Dutta, Harini Venkataganesh, Paul E. Love
DNA methylation is an important gene regulatory mechanism that controls many biological processes, including random chromosome X-inactivation in females, genomic imprinting, and maintenance of genomic stability [15]. In mammals, DNA can be methylated on the carbon-5 position of the cytosine ring by DNA methyltransferases (DNMTs), generating 5-methylcytosine (5mC). Such methylated cytosines are usually located in CpG dinucleotides (i.e. a cytosine next to a guanine) [15]. Most CpG sites in the genome are methylated except for those found clustered together in regions known as CpG islands, some of which are found near promoter regions of transcriptionally active genes. When the CpG islands near the transcription start sites (TSS) become methylated, then such genes are often stably silenced (Figure 1). Recently, one study showed that there are some TFs (OCT4, HOXB13) that prefer CpG-methylated sequences [16]. Most of these TFs belong to the extended homeodomain family and structural analysis has revealed that homeodomain specificity for methylcytosine depends on direct hydrophobic interactions with the 5mC [16]. DNMT1 is known to preserve the methylation pattern of genes after every replication cycle. It binds hemi-methylated DNA and methylates the newly synthesized unmethylated strand. DNMT3A and DNMT3B can recognize both unmethylated and hemi-methylated DNA so as to establish de-novo methylation [17]. There are enzymes that can erase preexisting DNA methylation. The ten-eleven translocation protein family (TET1-3) functions to oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidizes the intermediate product to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) [18]. The oxidized products of 5mC can be replaced by unmethylated cytosines through thymine DNA glycosylase (TDG)-mediated base excision repair and this leads to activation of gene expression [18, 19].