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Statistical Considerations and Biological Mechanisms Underlying Individual Differences in Adaptations to Exercise Training
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Jacob T. Bonafiglia, Hashim Islam, Nir Eynon, Brendon J. Gurd
The term epigenetics translates to “in addition to changes in genetic sequence” and refers to chemical modifications to DNA (such as DNA methylation) that regulate the expression of genes without altering the underlying DNA sequence, which can ultimately result in downstream changes in protein expression (10). There are two main types of epigenetic modifications (37). First, DNA methylation involves the addition of methyl groups directly to the DNA sequence by DNA methyltransferases (50). DNA methylation results in decreased transcription of the targeted gene, whereas DNA demethylation (or hypomethylation), a process regulated by ten-eleven translocation enzymes (50), increases gene transcription (see 58 for details). The second epigenetic process is histone modification, which involves post-translational modifications to histones (the protein forming the nucleosome core and providing structural stability) that ultimately affect transcription by allowing or inhibiting the transcriptional machinery access to promoter regions of target genes (50). Although not often considered an epigenetic process (37), the actions of non-coding RNAs (such as micro RNA) can also influence gene expression without altering DNA sequence. Collectively, DNA (de)methylation, histone modification, and non-coding RNAs influence gene expression and may therefore play important roles in the adaptive process to exercise (37, 50, 83, 85).
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].
Role of Ascorbate and Dehydroascorbic Acid in Metabolic Integration of the Cell
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Gábor Bánhegyi, András Szarka, József Mandl
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].
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].
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.
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.