China
Africa
Explore chapters and articles related to this topic
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
This is a difficult question to answer given that we have already said epigenetics is a means to respond to the environment, provide hormesis and achieve homeostasis. Inbred animals are often used in safety studies for the very reason that the stable genome provides more homogenous responses to insults and therefore reduces the statistical burden required to test the null hypothesis. To understand whether deviations from baseline for epigenetic changes are important in determining hazard of the test material, it is necessary to understand the baseline and how much, and what type, of deviation from that baseline is deleterious. Realising the importance of this the CEFIC/LRI programme funded a project (C3) in 2014 [26] to look at the baseline methylation patterns across multiple tissues in two rodent strains commonly used for chemical testing. This work showed that there are differences in methylation patterns between gender and strains (Wistar and Sprague Dawley), but within the strains and gender there is relative homogeneity [27]. The study also looked at the 5-hydroxymethylation cytosine modification. As described earlier, the removal of methylation marks begins with conversion of 5-methyl cytosine to 5-hydroxymethylcytosine. Thomson et al. [27] found that the 5-hydroxymethylation cytosine marks are more variable in gene bodies between gender and species and as such might be a better marker for environmentally mediated epigenetic change than the 5-methylcytosine itself.
Nanofluidic Transport and Sensing in Biological and Artificial Nanopores
Published in Yuri L. Lyubchenko, An Introduction to Single Molecule Biophysics, 2017
The concept of enzyme-regulated DNA ratcheting is shown in Figure 6.15 (Carson and Wanunu 2015). In one scheme that involves phi29 DNA polymerase (phi29-pol) as the ratchet, DNA that is bound to a phi29-pol is first electrophoretically threaded into the pore, which results in unzipping of a blocking oligomer that was designed to prevent DNA synthesis in solution. Once unzipped, the polymerase can then back-track the DNA through the pore, base by base, by replicating the template strand. (This requires nucleotide triphosphates and divalent ions, typically Mg2+, in the buffer solution.) As each base is incorporated into the growing strand, the template DNA moves up the pore (see Figure 6.15a). Interestingly, during the first step in which electrophoretic force is used to unzip the blocking oligo, a discrete set of signals can be observed that correspond to the sequence of the DNA. This is confirmed by comparing the signal during the force unwinding step to the signal during polymerase-based synthesis, which upon inspection appear as exact mirror images of each other (compare “voltage-driven zipper” to “replication-driven ratchet” in Figure 6.15b). When Jens Gundlach and his team later repeated the Akeson experiment using a superior nanopore to hemolysin, MspA, the current signals from the DNA sequence appear much more well resolved (Manrao et al. 2012). This is due to the thinner geometry of the nanopore, which allows superior readout (see Figure 6.15c). An immediate application of this method for epigenetic analysis is shown in Figure 6.15d, in which control DNA samples that contain the modified bases 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC) were distinguished (Laszlo et al. 2013). Undoubtedly, the enzyme-driven motion of DNA is the method of choice for sequencing, as it allows high-precision measurements of each DNA sequence in the pore at a given time. Other enzymes can be used to achieve this regulated motion of DNA. DNA helicases used for base-by-base unwinding, such as Hel308 (Derrington et al. 2015), for example, have demonstrated comparable or better results to the polymerase method.
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).
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.
DNA methylation modifications induced by hexavalent chromium
Published in Journal of Environmental Science and Health, Part C, 2019
Xinnian Guo, Lingfang Feng, Bernardo Lemos, Jianlin Lou
DNA methyl transferases (DNMTs) catalyze DNA methylation reactions and are typically up-regulated by oxidative stress. Mammals have five DNMTs: DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L. Among these enzymes, DNMT1 and DNMT3B will form the DNMT-Containing Complexes with Sirtuin1 (SIRT1) and polycomb repressive complex 4 (PRC4) after hydrogen peroxide (H2O2) treatment. SIRT1 can interact with DNMT1 and other proteins during the process of DNA damage.40,41 Additionally, PRC4 is another important protein of the complexes, which have been proven to interact with DNMTs in response to H2O2-induced DNA damage, probably increasing DNA methylation. Maybe that is the reason for DNMT-Containing Complexes localization at sites of H2O2-induced DNA damage. However, it is still unclear whether the expression of DNMTs is related to the formation of DNMT-Containing Complexes. As already reported, dynamic regulation of DNA methylation is achieved through a cyclic enzymatic cascade mainly comprised of DNMTs and TET dioxygenases, which converts cytosine (C) to 5mC and 5mC to 5-hydroxymethylcytosine (5-hmC), respectively.42 Furthermore, 5-hmC can be converted back to cytosine (C) in unknown ways. Thus, the increased levels of DNMTs and DNMT-Containing Complexes may contribute to the changes of DNA methylation status by promoting the conversion of cytosine (C) to 5mC. Previous studies demonstrated that under the condition of oxidative stress, deoxyriboguanosine monophosphate (dGMP) can develop into 8-hydroxydeoxyguanosine (8-OHdG), which is a marker of DNA oxidative damage. Meanwhile, 8-OHdG can also negatively affect DNA methylation of nearby cytosines. On the other hand, 8-OHdG is related to demethylation coupled with oxidative damage repair followed by global hypomethylation.35 Furthermore, the level of DNA methylation can be decreased by the conversion of 5mC to 5hmC, which may take place either passively or actively. Under these circumstances, one can envision that both regional DNA hypermethylation and global DNA methylation may occur through oxidative stress after chromium exposure.