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The Role of Epigenetics in Skeletal Muscle Adaptations to Exercise and 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
Interestingly, metabolites that are ordinarily TCA-cycle intermediates are important regulators of the TET enzymes that enzymatically remove DNA methylation. The TET enzymes require α-ketoglutarate as a co-factor for full activity (49). Although α-ketoglutarate is an integral component of the TCA cycle, it can also be synthesized in the cytosol/nuclear compartments from glutamate via transamination. Therefore, enhanced α-ketoglutarate synthesis could conceivably reduce DNA methylation. Whether this mechanism contributes to exercise-induced DNA hypomethylation remains to be determined. Furthermore, mutant isocitrate dehydrogenase enzymes, which are often observed in certain cancers, can also produce 2-hydroxyglutarate (2-HG) from α-ketoglutarate (49). The 2-HG metabolite inhibits TET function and has been associated with DNA hypermethylation and repression of gene expression (49). Whether exercise training influences any of these metabolic mechanisms regulating epigenetics remains to be determined. These studies highlight the emerging interactions between metabolism and epigenetics, which will be an important area of study in the future to further our understanding of the molecular mechanisms mediating exercise adaptations in skeletal muscle.
Ascorbate as an Enzyme Cofactor
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Margreet C.M. Vissers, Andrew B. Das
The methylation of DNA cytosine (5mC) at gene promoters is usually associated with transcriptional silencing, and the dynamic regulation of gene expression requires the controlled removal of 5mC [201,206]. This process is mediated by the ten-eleven translocase (TET) enzymes, members of the 2-OGDD family which successively oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), leading to excision repair and effective demethylation (Table 5.1) [84,207,208]. In addition to its role as an intermediate in the demethylation process, 5hmC can be a stable epigenetic marker and is relatively abundant at ∼0.032% of the genome in embryonic tissues and up to 0.6% in Purkinje cells in the cerebellum [209]. Its presence is associated with altered levels of gene transcription [85]. It can engage its own binding proteins and is most abundant at enhancers, gene bodies, promoters and CpG islands with lower GC content, and accumulates on euchromatin marked by H3K4me2/3 [210–213]. These data are indicative of the TET enzymes having complex regulatory and functional epigenetic roles via generation of 5hmC.
Epigenetics of exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Daniel C. Turner, Robert A. Seaborne, Adam P. Sharples
In contrast, the removal of a CH3 methyl group from cytosine nucleotides results in 5-hydromethylcytosine (5-hmC) and therefore results in reduced methylation, also known as ‘hypo’-methylation or demethylation. Such biochemical processes are catalysed by several key enzymes that determine whether CpG sites are either methylated or demethylated. For example, specific enzymes are required to either promote, maintain or remove methyl groups and are sometimes referred to as ‘writers’, ‘readers’ and ‘erasers’ respectively (see (5) for a detailed review). The DNA methyltransferases (DNMTs), DNMT3a, DNMT3b and DNMT1, are the main family of enzymes that promote increased DNA methylation (Figure 6.1) (8). The former two enzymes (DNMT3a and DNMT3b) are essential for establishing de novo or ‘new’ methylation, whereas the latter DNMT1 enzyme is most responsible for maintaining methylation during cell division, enabling daughter cells to preserve methylation profiles that would otherwise be lost without DNMT1 enzyme activity (9, 10). Indeed, a lack of DNMT1 enzyme activity results in the passive loss of DNA methylation during DNA replication. However, another set of important enzymes, known as the ten-eleven translocation (TET) enzymes (TET1, 2 and 3), directly catalyse the removal of methyl groups and this is therefore considered an ‘active’ mechanism responsible for reduced methylation/hypomethylation (11, 12) (Figure 6.1). The extent to which DNMT and TET enzymes are differentially activated to modulate the DNA methylation response after endurance and resistance exercises is discussed below in this chapter.
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.
Acute inhalation of ozone induces DNA methylation of apelin in lungs of Long-Evans rats
Published in Inhalation Toxicology, 2018
Colette N. Miller, Janice A. Dye, Mette C. Schladweiler, Judy H. Richards, Allen D. Ledbetter, Erica J. Stewart, Urmila P. Kodavanti
The TET enzymes are responsible for demethylation of CpG islands and as such, are important in the process of gene activation. Unlike what was observed in the DNMTs, ozone exposure did not alter Tet1, Tet2 or Tet3 mRNA expression (Figure 2(C)). Likewise, the activity of TET enzymes in the lungs (Figure 2(D)) was not affected by ozone exposure.
DL-propargylglycine administration inhibits TET2 and FOXP3 expression and alleviates symptoms of neonatal Cows’ milk allergy in mouse model
Published in Autoimmunity, 2020
Beibei Sun, Dongjin Feng, Guangmeng Wang, Xiaohong Yu, Zhongmao Dong, Ling Gao
Epigenetic modification, especially DNA methylation, is essential for FOXP3 expression. During FOXP3 expression, the CpG island of its transcriptional regulatory region that located on the second conserved non-coding sequence (CNS2) which is also known as the Treg-specific demethylated region (TSDR), is fully demethylated [10,12]. Hypermethylation of the FoxP3 TSDR has been associated with reduced Treg function [10,15]. Furthermore, FOXP3 TSDR demethylation in PBMCs correlated with suppression of atopic sensitisation and asthma in infants [12], and FOXP3 TSDR methylation in Tregs decreased during oral tolerance acquisition in patients with peanut allergy undergoing oral immunotherapy [10,12,13]. DNA methylation is in the regulation of DNA methyltransferases (for example DNMTs proteins) and DNA demethylase that contains Ten-eleven translocation (TET) family protein TET1-3. TET enzymes oxidise 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidised methylcytosines, intermediates in DNA demethylation [15–18]. Accumulated shreds of evidence have revealed a regulatory function of TET proteins in the regulation of FOXP3 expression [15,17,19–23]. In the Tregs of allergic rhinitis, down-regulation of Tet2 is associated with Foxp3 TSDR hypermethylation, and the binding of TET2 on the FOXP3 CNS2 was significantly increased upon strong TCR stimulation [21]. On mechanism, TET proteins are recruited to the CpG motifs of CNS2 by IL2, and then protects it from re-methylation by DNA methyltransferases and prevents Tregs from losing Foxp3 expression under inflammatory conditions [24]. Thus, clinical interventions in the TET proteins expression and then FOXP3 methylation could be a desirable strategy for CMA therapy. Hydrogen sulphide (H2S) was reported that required for maintaining that expression of TET1 and TET2, and then Foxp3 Treg cell differentiation and function [24]. H2S maintained the expression of TET1 and TET2 by sulfhydrating nuclear transcription factor Y subunit beta (NFYB) to facilitate its binding to Tet1 and Tet2 promoters [24]. Therefore, we reasonably suspected that the blockage in H2S production using propargylglycine (PAG) administration, a fundamental inhibitor of cystathionine γ-lyase (CSE) which catalyses the production of H2S, could beneficial for CMA patients.