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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).
Vitamin C and Somatic Cell Reprogramming
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Enhanced iPSC reprogramming and DNA demethylation induced by vitamin C are also mediated by the TET proteins [18,19]. The TETs (TET1-3) are a subfamily of α-KGDDs that catalyze the hydroxylation of 5-methylcytosine (5 mC) residues in DNA to generate 5-hydroxymethylcytosine (5 hmC) [37], and through successive oxidation reactions, 5-formylcytosine (5 fC) and 5-carboxylcytosine (5 CaC). The oxidative products of 5 mC catalyzed by TET proteins can be stable modifications in the genome or transient modifications that provide a trigger for active or passive DNA demethylation [37–39].
The Epigenetic Role of Vitamin C in Neurological Development and Disease
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Recent work uncovered the answer to this question after discovering that the ten-eleven translocation 1 (TET1) enzyme converted 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) in cultured cells [3]. Subsequent work demonstrated that TET enzymes further convert 5hmC to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), two transient modifications that are quickly excised by the DNA base excision repair pathway and ultimately replaced by unmodified cytosine [4,5]. This cycle of conversion from cytosine→5mC→5hmC→5fC→5caC→cytosine comprises active TET-mediated DNA demethylation. TET enzymes belong to the Fe(II)- and 2-oxoglutarate (2OG, also known as α-ketoglutarate)-dependent dioxygenase superfamily, a diverse class of enzymes found in practically all evolutionary taxa [6]. Although their functions greatly vary, each member of this family requires both 2OG and molecular oxygen as cosubstrates for the hydroxylation reaction and utilize Fe(II) as a cofactor. TET enzymes initiate active DNA demethylation by binding molecular oxygen to Fe(II) to form a ferryl iron intermediate Fe(IV), which then hydroxylates 5mC to 5hmC [7,8]. This reaction, however, results in ferric Fe(III) that is unusable by TETs. Without the ability to convert Fe(III) back to catalytically active Fe(II), TET enzymes are stalled and are unable to continue active DNA demethylation. To continue this process, TET enzymes require an additional cofactor capable of reducing Fe(III) back to its catalytically active form, and thus emerges the role of vitamin C.
Epigenetic regulation in Alzheimer’s disease: is it a potential therapeutic target?
Published in Expert Opinion on Therapeutic Targets, 2021
5-Hydroxymethylcytosine (5-hmC) results from the oxidation of 5-mC mediated by members of the ten-eleven translocation (TET) protein family, and can be further oxidized to 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC) that are excised from the DNA and replaced with unmodified cytosine by DNA base excision repair enzymes, so that 5-hmC has long been considered only as an intermediate of cytosine demethylation processes [15]. However, increasing evidence suggests that 5-hmC is another stable epigenetic mark in mammalian brain regions where it binds to proteins important for neuronal function and development, and altered brain 5-hmC levels have been observed in neurodevelopmental and neurodegenerative disorders [15,16]. Overall, it is emerging that DNA methylation and hydroxymethylation marks orchestrate the genome architecture and gene expression levels during neuronal differentiation and function, thus playing fundamental roles in brain development and memory formation, and their impairment is increasingly implicated in neurodevelopmental, neurobehavioral and neurodegenerative disorders [13–16].
Characterization of DNA hydroxymethylation profile in cervical cancer
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Jing Wang, Yi Su, Yongju Tian, Yan Ding, Xiuli Wang
DNA methylation, the most widely studied epigenetic regulation mainly occurs at CpG loci or islands via transferring a methyl group to cytosines to generate 5-methylcytosine (5mC) by methyltransferase DNMT family. The presence of aberrant DNA methylation including hypo- and hypermethylation in cervical cancer and high-grade cervical intraepithelial neoplasia suggests that most genes are hypermethylated [4]. However, direct removal of the methyl from 5mC is infeasible in terms of the energy consumption for DNA demethylation. Recent studies revealed that 5mC could be further oxidized into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5foC), and 5-carboxylcytosine (5caC) by ten-eleven translocation (TET) proteins and finally return to regular cytosine for one manner of DNA demethylation process [5–7]. Thus, 5hmC, a more stable epigenetic mark compared to 5mC, plays a crucial role in methylation recycle maintenance as an intermediate [8].
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].