Exercise, Metabolism and Oxidative Stress in the Epigenetic Landscape
James N. Cobley, Gareth W. Davison in Oxidative Eustress in Exercise Physiology, 2022
DNA methylation occurs in two contexts aided by three DNA methyltransferase (DNMT) enzymes. DNMT1 is a maintenance methyltransferase, which recognises hemimethylated DNA to form a symmetrically modified duplex during DNA replication, while DNMT3A and DNMT3B are primarily de novo enzymes that deposit CH3 marks on previously unmodified cytosines (Okano et al., 1999; Grurnbaum et al., 1982). Methylation of DNA occurs with the addition of CH3 at the C5 position of the nucleoside cytosine, forming 5-methylcytosine (5mC) on CpG dinucleotides (80% of cytosine residues in CpG dinucleotides are methylated at position 5, Davison et al., 2021). The CpG dinucleotide is unique in that it only occurs at a low frequency, while simultaneously converging into CpG islands (CGI) extending for 300–3,000 base pairs, mainly in regulatory elements of genes such as enhancer and promoter regions (Hitchler and Domann, 2021). Located up- and downstream of CpG islands are CpG shores and CpG shelves which display greater tissue-specific methylation profiles (Seaborne and Sharples, 2020). Methylation is absent in CGI AT promoter regions with active transcription. However, when promoter-associated CGI are methylated, transcription is silenced (Bird, 2007). More recently, it has been shown by a number of genome-wide and functional studies that DNA methylation in the gene body also facilitates transcription (Wu et al., 2010; Neri et al., 2013; Irwin et al., 2014).
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
The above-mentioned hypomethylation promotes the malignant degeneration of cells due to favoring a reorganization of chromosomal sections. The most important mechanism of epigenetic regulation is the methylation of DNA by DNA-methyltransferases. It has been found that hypermethylation (methylation of cytosine residues of DNA) of gene-promoter regions, leading to transcriptional repression of tumor suppressor genes the protein products of which such as CDK-inhibitor 2A and RB1 (retinoblastoma protein) decelerate tumor progression, is a common feature of many cancers (Baylin and Jones, 2011). This also holds for global deacetylation. Histone deacetylases (HDACs) class I, II, and IV are Zn2+-dependent amidohydrolases removing an acetyl moiety from a lysine residue at the N-terminus of histone. Class III HDACs (sirturins) are NAD+-dependent. The catalytic action of HDACs enables the histones to wrap the DNA more tightly whereas acetylation of histones by acetyl transferases (HATs) transferring an acetyl group from acetyl-CoA to form ε-N-acetyl lysine normally results in an increase in gene expression, e.g., that of the tumor suppressor p53. Various HAT families are known that differ from each other in their reaction mechanism. The equilibrium of histone acetylation and deacetylation is important for a proper modulation of chromatin topology and regulation of gene transcription. For an excellent review of exploiting the epigenome to control cancer-promoting gene-expression programs, see Brien et al. (2016).
Statistical Considerations and Biological Mechanisms Underlying Individual Differences in Adaptations to Exercise Training
Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse in The Routledge Handbook on Biochemistry of Exercise, 2020
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).
DNA methyltransferase inhibitors increase NOD-like receptor activity and expression in a monocytic cell line
Published in Immunopharmacology and Immunotoxicology, 2022
Claire L. Feerick, Declan P. McKernan
DNA methylation and histone acetylation are the best-characterized contributors to the epigenome [17,18] and so are investigated here. DNA methylation, catalyzed by DNA methyltransferase enzymes, involves the addition of a methyl group onto cytosine residues, forming 5-methylcytosine [19]. It is generally accepted that methylation of cytosines in CpG dinucleotides-rich regions, referred to as ‘CpG islands,’ within the transcriptional start sites (TSSs) silences the downstream gene [17]. Histone acetylation is the addition of acetyl groups to lysine residues in histone proteins thereby neutralizing lysine’s positive charge, reducing their affinity for surrounding DNA, and thereby relaxing the chromatin and accommodating expression of underlying genes [20]. Histone acetylation status is maintained by a balance in the activity of two enzymes; histone acetyltransferases (HATs) and histone deacetylases (HDACs) [21]. Drugs targeting epigenetic modifying enzymes have recently been used in the treatment of certain cancers but the full extent of their effects have not been studied [22–26]. Previous work from our group has shown that pharmacological and genetic inhibition of such enzymes affected TLR responses in intestinal epithelial cells [27]. We hypothesized that drugs targeting epigenetic modifications may regulate NOD1/2 expression and pro-inflammatory activity in a monocytic cell line.
A 5-gene DNA methylation signature is a promising prognostic biomarker for early-stage cervical cancer
Published in Journal of Obstetrics and Gynaecology, 2022
Hongxia Chen, Hongying Li, Lei Wang, Yaxiong Li, ChunYan Yang
DNA methylation, a kind of epigenetic modification, may regulate gene expression and chromatin structure via DNA methyltransferase and demethylation enzymes (Li et al. 2017). It has been widely involved in the tumourigenesis and development of CC. For instance, HPV-mediated DNA methylation has been found in the aetiology of CC (Verlaat et al. 2018). The changes of gene expression due to DNA methylation have been widely observed in CC as well, including secreted frizzled-related proteins (SFRPs) (Lin et al. 2009), death-associated protein kinase 1 (DAPK-1), retinoic acid receptor beta (RARB), O6-methylguanine DNA methyltransferase (MGMT) (Sun et al. 2015), etc. Based on these novel findings, several gene methylation signatures could be used for risk stratification and early prognoses of CC patients. For example, Cai et al. (2020) identified a risk model that included a 10-gene methylation, which could discriminate CC patients of pathological stages I–III at different risk of mortality. Xu et al. (2019) identified four CC-specific methylation markers that were capable of distinguishing CC from normal tissues. Furthermore, Brebi et al. also revealed that the methylated changes of five genes could differentiate between CC and normal samples. Despite these remarkable findings, research on the DNA methylation signatures used for early-stage CC’s clinical prognosis was still limited.
Evaluation of the efficacy of an antioxidant combination for the modulation of metabolic, endocrine, and clinical parameters in patients with polycystic ovary syndrome
Published in Gynecological Endocrinology, 2023
Carmen Pingarrón Santofímia, Silvia Poyo Torcal, Helena López Verdú, Alexandra Henríquez Linares, Virginia Calvente Aguilar, Pablo Terol Sánchez, María Sol Martínez García, Pilar Lafuente González
In our study, a significant improvement of clinical and analytical indicators after 6 months of treatment with ALA + NAC + B6+SAMe can be associated with a dual mechanism of action: increasing insulin sensitivity through de novo synthesis of glutathione and modulating androgen action by improving DNA methylation by SAMe. Regarding the first mechanism, the regulation of insulin action depends on hepatic glutathione content. Modulating de novo synthesis of glutathione would help in the prevention of diabetes, as glutathione can block the glucose/reactive oxygen species-induced β-cell damages [18, 19]. With respect to the second mechanism, it is known that the promoter region of the androgen receptor is hypo-methylated in granulosa cells of women with PCOS [20]. In addition, granulosa cells isolated from PCOS patients show a 25% reduction in the level of 5-methylcytosine [21]. DNA methylation is catalyzed by a family of DNA methyltransferases that transfer a methyl group from SAMe to the fifth carbon of a cytosine residue to form 5-methylcytosine [22]. This could be related to the antiandrogen response seen in the present study. However, further investigation is required to elucidate the potential of SAMe in epigenetic modulation of the pathogenesis of PCOS.
Related Knowledge Centers
- Biochemistry
- Catalysis
- DNA
- DNA Methylation
- Enzyme
- Methyl Group
- S-Adenosyl Methionine
- DNA Adenine Methylase
- Site-Specific DNA-Methyltransferase
- 5-Methylcytosine