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Human physiology, hazards and health risks
Published in Stephen Battersby, Clay's Handbook of Environmental Health, 2023
Revati Phalkey, Naima Bradley, Alec Dobney, Virginia Murray, John O’Hagan, Mutahir Ahmad, Darren Addison, Tracy Gooding, Timothy W Gant, Emma L Marczylo, Caryn L Cox
Earlier we have discussed methylation of the cytosine base of DNA as an epigenetic mechanism. This is not the only mechanism of epigenetic regulation and while we do not have space to discuss the other methods it would be remiss if they were not mentioned. As briefly introduced earlier, there are generally considered to be three levels of epigenetic regulation. These involve modification to (a) the DNA itself by methylation of cytosine to form the so-called fifth base – 5-methylcytosine, (b) the histone proteins around which DNA is wound – histone modification, and (c) non-coding RNA species including, but not exclusively, microRNAs (miRNAs). Histone changes are one of the devices the cell has on hand to rapidly and transiently control gene expression. Modification of histone tails is essential to allow unwinding of DNA prior to transcription [13]. As post-translational modifications to histones are more transitory than those to the DNA itself, it has been proposed that they are used by the cell as a trial mechanism to establish if the resulting changes in gene expression are beneficial in response to an environmental factor. If found to be advantageous then the expression change is made more permanent by being converted into a new methylation pattern within the DNA.
Epigenetic control of cell fate and behavior
Published in David M. Gardiner, Regenerative Engineering and Developmental Biology, 2017
Today, we understand that these epigenetic patterns of expression are controlled through the mechanisms of DNA methylation, histone modifications, and several types of non-coding RNAs. DNA can be methylated at cytosine bases in eukaryotes, changing the identity of the base to 5-methylcytosine (Chen and Li 2004). This modification is typically observed in cytosine bases that are followed by a guanine base, known as CpG dinucleotide, as illustrated in Figure 18.2. DNA methylation is generally associated with transcriptional silencing; however, there is some evidence of transcriptional activation resulting from methylation (Wu et al. 2010). During the process of DNA methylation, methyl groups are transferred from the co-substrate S-adenosyl-L-methionine by various enzymes known as DNA methyltransferases (DNMTs). Figure 18.3 illustrates the activity of two classes of DNMTs. The DNMT1 class of methyltransferases is responsible for the maintenance of methylation patterns in DNA. In the process of cell division, DNMT1 follows the DNA replication machinery, reading the parent strand’s pattern of methylation and copying it faithfully onto the newly created daughter strand (Chen and Li 2004). In this way, a cell’s pattern of DNA methylation can be passed onto cellular progeny, in order to maintain specific patterns of gene expression. This is particularly important during the growth and homeostasis of tissues and organs. As cells turn over, new cells can be generated to perfectly replace lost cells in identity and function.
IDH1 and IDH2 Mutations as Novel Therapeutic Targets in Acute Myeloid Leukemia (AML): Current Perspectives
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Angelo Paci, Mael Heiblig, Christophe Willekens, Sophie Broutin, Mehdi Touat, Virginie Penard-Lacronique, Stéphane de Bottona
Methylation profile of several human malignancies showed that IDH1/2-mutant tumors display a typical CpG island methylator phenotype (CIMP) characterized by high degree of DNA hypermethylation in CpG-rich domains (Figueroa et al., 2010; Noushmehr et al., 2010; Lian et al., 2012). Hypermethylation is the dominant feature of IDH1/2-mutant acute myeloid leukemias (AMLs) and these mutants display similar DNA methylation profiles. Interestingly, cells mutant for TET2 that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in DNA (Ko et al., 2010; Ito et al., 2011) or for transcription factor Wilms’ tumor 1 (WT1), display an overlapping hypermethylation signature with IDH1/2-mutants cells (Figueroa et al., 2010; Rampal et al., 2014; Wang et al., 2015b). Such wide epigenetic modifications are associated with altered expression of genes involved in cellular differentiation, broad growth-suppressive activity in primary cells or established cell lines (Figueroa et al., 2010; Lu et al., 2013; Turcan et al., 2012; Saha et al., 2014; Kernytsky et al., 2015; Rohle et al., 2013) as in genetically engineering mouse models (Chen et al., 2013; Chaturvedi et al., 2013; Kats et al., 2014; Saha et al., 2014; Shih et al., 2017), thereby resulting in a block to cellular differentiation. Gene expression profile of large cohorts of gliomas and AMLs have shown that IDH1/2-mutant tumors display a distinct gene expression profile enriched for genes expressed in progenitor cells (Figueroa et al., 2010; Turcan et al., 2012; Noushmehr et al., 2010; Brat et al., 2015; Ceccarelli et al., 2016; Turcan et al., 2018). Hypermethylation can also compromise the binding of methylation-sensitive insulator proteins, which may result in the loss or change of insulation between topological DNA domains and aberrant gene activation, as recently demonstrated in IDH1-mutant gliomasphere models (Flavahan et al., 2016) and neural stem cells (Modrek et al., 2017). Importantly, there is a correlation between intracellular concentrations of D-2HG and the epigenetic effects in IDH-mutant tumors. Indeed, as D-2HG is a weak competitor of αKG, the phenotype of immature cell is only observed when a high level of accumulation of D-2HG is reached (Lu et al., 2013).
Animal models and mechanisms of tobacco smoke-induced chronic obstructive pulmonary disease (COPD)
Published in Journal of Toxicology and Environmental Health, Part B, 2023
Priya Upadhyay, Ching-Wen Wu, Alexa Pham, Amir A. Zeki, Christopher M. Royer, Urmila P. Kodavanti, Minoru Takeuchi, Hasan Bayram, Kent E. Pinkerton
In addition to RNA interference, other epigenetic modifications might be mediated by different mechanisms, including DNA methylation and histone modification, which might also play essential roles in COPD development. DNA methylation is a chemical modification that involves addition of a methyl group to cytosine residues in CpG dinucleotides, resulting in formation of 5-methylcytosine. DNA methylation might occur in promoter regions of genes, leading to gene silencing or reduced gene expression. In COPD, alterations in DNA methylation patterns were noted in genes involved in inflammation, oxidative stress, and tissue remodeling, which are critical processes in COPD pathogenesis (Alfahad et al. 2021). Previously Zeng et al. (2020) suggested that cigarette-induced oxidative stress plays a role in mediating pulmonary apoptosis and hypermethylation of the B-cell lymphoma/leukemia-2 (Bcl-2) promoter, an apoptosis regulator, in COPD through DNA methyltransferase enzyme 1 (DNMT1), a key DNA methyltransferase enzyme. Similarly, aberrant DNA methylation was reported to be a widespread occurrence in small airways of COPD patients and was associated with altered expression of genes and pathways related to COPD, such as NF-E2-related factor 2 oxidative response pathway (Vucic et al. 2014).
The deamination mechanism of the 5,6-dihydro-6-hydro-6-hydroxylcytosine and 5,6-dihydro-5-methyl-6-hydroxylcytosine under typical bisulfite conditions
Published in Molecular Physics, 2019
Lingxia Jin, Gongwei Qin, Caibin Zhao, Xiaohu Yu, Jiufu Lu, Hao Meng
DNA methylation usually involves addition of a methyl group to the C5 site of cytosine (Cyt), yielding 5-methylcytosine (5-MeCyt). 5-MeCyt has been proven to have an impact on a variety of cellular processes that affect development [1,2] and gene expression [3] as well as the development of various diseases [4]. 5-MeCyt is known to regulate gene transcription and thereby affect tumorigenesis [5,6]. The level of epigenetic methylation has to be precisely regulated in eukaryotic genomes, since changes of the methylation pattern lead to severe genetic malfunctions [7]. Therefore, the detection of the occurrence and distribution of 5-MeCyt in the genome is very crucial to serve as an important biomarker for diagnosis as well as disease therapy [8–10]. It is well known that both Cyt and 5-MeCyt are complementary to guanine, but the discrimination of them is much more complex. To date, although many of those chemical and physical methods were used to discriminate between Cyt and 5-MeCyt, the method of bisulfite sequencing is simple and inexpensive [11–15]. It has been regarded as the gold standard for 5-MeCyt detection and therefore widely used to detect 5-MeCyt at single base resolution in a large variety of cell types and disease models. This method is based on the selective bisulfite-mediated deamination of Cyt to uracil in the presence of 5-MeCyt, which remains unchanged as a result of slower deamination [16]. The sites of epigenetic markers can be revealed by comparison of the output of conventional sequencing methods before and after bisulfite treatment, as Cyt will be sequenced as thymine (T), and 5-MeCyt as Cyt [17].
Effects of C5-substituent group on the hydrogen peroxide-mediated tautomerisation of protonated cytosine: a theoretical perspective
Published in Molecular Physics, 2018
Lingxia Jin, Shengnan Shi, Yang Zhao, Liyang Luo, Caibin Zhao, Jiufu Lu, Min Jiang
Furthermore, noted that 5-methylcytosine (5-meCyt) is an epigenetic DNA mark that plays important roles in gene silencing and genome stability [28], which can be oxidised to 5-hydroxymethylcytosine (5-hmCyt) by the ten-eleven translocation enzyme family [29]. Further oxidation of 5-hmCyt in DNA may result in the formation of 5-formylcytosine (5-fCyt) and 5-carboxycytosine (5-caCyt) [30]. As is well known, the various substituents of their C5 sites for the pyrimidine derivatives have certain affected on the electron distributions of their pyrimidine rings, raising that the question of whether these newfound cytosine derived DNA modification may affect the isomerisation of protonated cytosine in the presence of H2O2.