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DNA methylation analysis using bisulfite sequencing data
Published in Altuna Akalin, Computational Genomics with R, 2020
DNA methylation is established by DNA methyltransferases DNMT3A and DNMT3B in combination with DNMT3L and maintained through cell division by the methyltransferase DNMT1 and associated proteins. DNMT3a and DNMT3b are in charge of the de novo methylation during early development. Loss of 5mC can be achieved passively by dilution during replication or exclusion of DNMT1 from the nucleus. Recent discoveries of the ten-eleven translocation (TET) family of proteins and their ability to convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) in vertebrates provide a path for catalyzed active DNA demethylation (Tahiliani et al., 2009). Iterative oxidations of 5hmC catalyzed by TET result in 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5caC mark is excised from DNA by G/T mismatch-specific thymine-DNA glycosylase (TDG), which as a result reverts cytosine residue to its unmodified state (He et al., 2011). Apart from these, mainly bacteria, but possibly higher eukaryotes, contain base modifications on bases other than cytosine, such as methylated adenine or guanine (Clark et al., 2011).
Vitamin C in Immune Cell Function
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Abel Ang, Margreet C.M. Vissers, Juliet M. Pullar
In mammals, one of the most widespread epigenetic modifications is DNA cytosine methylation, a modification that generally results in silencing of gene expression [138,139]. This modification can be actively reversed by the Tet enzymes that catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), potentially a stable epigenetic mark in itself [138], or initiate the generation of 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which results in active regeneration of unmarked cytosine by excision-repair mechanisms [140]. Ascorbate availability has been shown to markedly enhance Tet activity [141,142] through its cofactor function, likely maintaining the active site Fe2+ of these dioxygenases [143]. Although other reducing agents could reduce Fe3+ and promote TET activity in a cell free system, ascorbate was shown to be the most efficient [143], and glutathione was incapable of increasing murine embryonic TET activity compared to equimolar ascorbate [141,142]. The Jumonji C domain-containing histone demethylases (JHDMs) are also members of the Fe- and 2-oxoglutarate dependent dioxygenase family, and similarly to TETs, full enzyme activity of JHDMs occurs when ascorbate is present [144,145]. The JHDMs are the third and largest class of demethylase enzymes, capable of removing all three histone lysine-methylation states through oxidative reactions [145].
The Role of Nutraceuticals in the Placental Growth, Development and Function
Published in Priyanka Bhatt, Maryam Sadat Miraghajani, Sarvadaman Pathak, Yashwant Pathak, Nutraceuticals for Prenatal, Maternal and Offspring’s Nutritional Health, 2019
Maryam Miraghajani, Michael E. Symonds
Oxidative stress is referred to as an imbalance between the generation of reactive oxygen species (ROS) or reactive nitrogen species (RNS) and their clearance by defensive antioxidants. Oxidative stress is generated during normal placental development and promotes replication, differentiation and maturation of cells. However, when the supply of antioxidant micronutrients is limited, exaggerated oxidative stress occurs that seems to be linked with pregnancy-related disorders through pathways such as an imbalance in the autophagy and apoptosis (81, 82). Antioxidants such as vitamins C and E are often investigated as promising therapies to reduce oxidative stress during pregnancy and in the placental level, and their beneficial effects have been shown in some but not all trials. Administration of these vitamins can mediate oxidative stress in human placenta through many pathways, including blocked activation of the p38 and stress-activated mitogen-activated protein kinase (MAPK) and nuclear factor-κB (48) Also they reduce cyclooxygenase-2 expression, tumor necrosis factor-α and interleukin-1β secretion, and apoptosis (48). As well as the well-known antioxidant function of vitamin C in the placenta, it serves as an essential cofactor to numerous monooxygenases and dioxygenases, including the ten-eleven translocation (TET) enzyme family. This catalyzes the hydroxylation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in the active process of DNA demethylation (83, 84). However, there is a lack of human studies in this field.
Dietary Phytochemicals as a Potential Source for Targeting Cancer Stem Cells
Published in Cancer Investigation, 2021
Prasath Manogaran, Devan Umapathy, Manochitra Karthikeyan, Karthikkumar Venkatachalam, Anbu Singaravelu
Fisetin or 3,7,3′,4′‐tetrahydroxyflavone is a natural flavonol. It is found in various plant sources with antioxidant and anticancer properties.5-Hydroxymethylcytosine (5hmC) is an oxidative product of 5-methylcytosine (5mC), catalyzed by the ten-eleven translocation (TET) family of enzymes, and TET enzymes are mutated in several types of cancer, affecting their activity and likely altering genomic 5hmC and 5mC patterns (77–79). Renal cancer tissues and CD44/CD105 positive HuRCSCs (Human Renal cancer stem cells) show high TET1 protein expression. The incidence of renal cancerwas estimated in 2020, as per that the 73,750 new cases and 14,830 deaths were expected in the United States (28). In treatment with Fisetin to HuR CSCs leads to inhibit HuRCSC cell division and proliferation, invasion, in vivo tumorigenesis and angiogenesis. Apart from that fisetin inhibits the non-small lung cancer cells even at deficient concentration, epithelial to mesenchymal transition and invasion marker MMP-2 and down regulates the stem cell signature like markers such as CD24 and CD133. Furthermore, the fisetin treatment altered multiple signaling pathways such as β-catenin, NF-κB, EGFRand STAT-3 (80).
Intersections and Clinical Translations of Diabetes Mellitus with Cancer Promotion, Progression and Prognosis
Published in Postgraduate Medicine, 2019
Stanley S. Schwartz, Struan F.A. Grant, Mary E. Herman
The composite of the research described above provides compelling, coincidental evidence linking hyperglycemia with cancer. A direct line between hyperglycemia to oncogenesis has been charted by the recent characterization of a ‘phospho-switch’ in the DNA 5-hydroxymethylome by Wu and coworkers. Their research showed that elevated glucose levels destabilize the TET2 tumor suppressor protein [41]. The phosphorylation state of TET2 is controlled at serine 99 by AMP-activated kinase, a signaling pathway that is shared with glucose regulation. The strength of this association is supported by the finding that metformin – an antidiabetes agent associated with reduced cancer outcomes in some studies – was found to guard TET2 levels by reinstating/maintaining the glucose/AMP-activated kinase/TET2/5-hydroxymethylcytosine axis [41]. 5-hydroxymethylcytosine is also particularly noteworthy for its intimate relation to epigenetic state. Interestingly, metformin has previously been shown to stabilize epigenetic status (through histone modifications, DNA and/or RNA methylation, and noncoding RNA) (reviewed by Yu al. 2017 [42]). Therefore, TET2 represents a discrete molecular link between dysglycemia and cancer; likely, many more direct links exist to support the contention that cellular pathways exist at the crossroads between energy metabolism, and, tumorigenesis and tumor growth.
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].