Methylome and epigenetic markers
Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos in New Technologies and Perinatal Medicine, 2019
DNA methylation is mediated by DNA methyl transferases (DNMT), which are enzymes responsible for catalyzing, recognizing, adding, and removing methyl groups. They are separated into two main classes: writers and erasers. Writers catalyze the addition of the methyl group onto cytosine residues, and erasers are associated with methyl group modification and removal. Specifically, DNMT1 is responsible for maintaining the heritable methyl group on the cytosine residues and has a preference for hemimethylated CpG sites generated by DNA replication (5). DNMT3A and DNMT3B are de novo methyltransferases responsible for methylating CpGs missed by DNMT1 (6,7). When DNA demethylation is required, either a passive or an active demethylation process takes place. Passive demethylation involves the inhibition of DNMT1 during cell replication in dividing cells. Active DNA demethylation involves enzymatic reactions to remove the methyl group from the cytosine residues, and it occurs in both dividing and nondividing cells (8). This mechanism allows for the embryonic development by controlling expression of genes at specific times and tissues.
Role of Ascorbate and Dehydroascorbic Acid in Metabolic Integration of the Cell
Qi Chen, Margreet C.M. Vissers in Vitamin C, 2020
ε-N-trimethyl-l-lysine hydroxylase and β-butyrobetaine hydroxylase, enzymes necessary for synthesis of carnitine, seem to be localized to the mitochondria and cytosol. Carnitine is essential for the transport of fatty acids into mitochondria for β-oxidation and consequent ATP generation [66]. However, the subcellular localization of 4-hydroxyphenylpyruvate dioxygenase, the enzyme that participates in the catabolism of tyrosine, is less known. In the nucleoplasm Fe(II)/2-oxoglutarate–dependent dioxygenases are involved in the epigenetic regulation of gene expression by demethylating histones and DNA [55]. Enzymes that demethylate histones mainly belong to the Jumonji protein family conserved from yeast to humans with a common jmjC functional domain [82]. DNA demethylation occurs at the methyl group of 5-methylcytosine via subsequent oxidative steps catalyzed by the dioxygenases of the ten-eleven translocation (TET) family [35,45].
Epigenetic considerations in preimplantation mammalian embryos
David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham in Textbook of Assisted Reproductive Techniques, 2017
In germ cells, heterochromatin undergoes significant changes in terms of epigenetic modifications, with major changes in down-regulation of H3K9me2 and up-regulation of H3K27me3 and an increase in histone acetylation and H3K4me3, which are histone marks associated with euchromatin (14). Changes in germ cells have been reviewed previously (15, 16) and are not specifically addressed here. These changes are likely to prepare the germ cells to successfully undergo subsequent epigenetic reprogramming after moving into the genital ridges. In the gonads (embryonic day 11.5 = E11.5 in the mouse), germ cells undergo a series of epigenetic reprogramming steps including DNA methylation, changes in chromatin structure, and genome-wide histone replacement, resulting in loss of a variety of histone modification marks (14, 17). Genome-wide DNA demethylation is an active process and is independent of replication (14), as evidenced by it occurring during the G2 cell cycle stage. It occurs prior to the onset of global chromatin changes and includes transient loss of H3K9me3, H3K27me3, and H2A/H4 R3me2s, as well as other histone modification marks.
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 role of pharmacogenomics in adverse drug reactions
Published in Expert Review of Clinical Pharmacology, 2019
Ramón Cacabelos, Natalia Cacabelos, Juan C. Carril
DNA demethylation can be produced by at least 3 enzyme families: (i) the ten-eleven translocation (TET) family, mediating the conversion of 5mC into 5hmC; (ii) the AID/APOBEC family, acting as mediators of 5mC or 5hmC deamination; and (iii) the BER (base excision repair) glycosylase family involved in DNA repair [27]. The DNA demethylation pathway plays a significant role in DNA epigenetics. This pathway removes the methyl group from cytosine, which is involved in the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) by ten-eleven translocation (TET) proteins. Then, 5-hmC can be iteratively oxidized to generate 5-formylcytosine and 5-carboxylcytosine [61]. The oxidation of 5-methylcytosine can result in three chemically distinct species: 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine [62].
Emerging DNA methylation inhibitors for cancer therapy: challenges and prospects
Published in Expert Review of Precision Medicine and Drug Development, 2019
Aurora Gonzalez-Fierro, Alfonso Dueñas-González
Since DNA methylation is dynamic, mammalian cells also possess the ability to remove these marks. Passive DNA demethylation was the first to be described. As it is passive, it depends on DNA replication and cell division plus the subsequent lack of action of DNA methylation maintenance pathways. On the contrary, active DNA demethylation is replication-independent and occurs through the active enzymatic removal of the methylcytosine [27]. Among DNA demethylases, the enzyme activation-induced cytidine deaminase (AID) deaminate 5-mC yielding thymidine that is replaced by an unmethylated cytosine by the base-excision repair (BER) pathway. Thus, AID may promote aberrant gene expression by decreasing the promoter DNA methylation of specific genes [28,29]. The family of tet1, tet2, and tet3 (ten-eleven translocation) proteins are also considered active DNA demethylases. These enzymes carry out the hydroxylation of 5-mC to 5-hmC [30], 5-hmC, in turn, is replaced with an unmethylated cytosine by the BER pathway [31]. Recent data demonstrate that several proteins bind to 5-hmC, revealing the possibility that specific proteins may be able to interpret the 5-hmC epigenetic mark and subsequently influence chromatin structure and gene expression [32,33]. Taken together, the establishment and maintenance model of DNA methylation is likely an oversimplification of what actually occurs and all DNMTs in concert with tet enzymes, regulate DNA methylation levels through a dynamic equilibrium of site-specific gain and loss of methylation during development and health and disease conditions.
Related Knowledge Centers
- Cpg Site
- Cytosine
- Demethylation
- Directionality
- DNA Methyltransferase
- DNA Sequencing
- Methyl Group
- Molecular Biology
- Guanine
- 5-Methylcytosine