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Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
P. M. Aswathy, C. M. Shafeeque, Moinak Banerjee
One of the best-studied epigenetic modifications is DNA methylation, which refers to the binding of a methyl group (–CH3) to the carbon in position 5 of a cytosine moiety, resulting in the formation of 5-methylcytosine (5mC). The classic functions of DNA methylation are genomic imprinting, X-chromosome inactivation in mammalian females, and gene silencing. This reaction occurs mostly at so-called CpG islands and is catalyzed by enzymes known as DNA methyltransferases (DNMTs). DNMTs are of four types, namely DNMT1, DNMT2, DNMT3a, and DNMT3b. DNA methylation appears to be frequently involved in the processes associated with both healthy and diseased aging, particularly in neurological and neurodegenerative diseases. Finally, the 5mC can be converted into 5-hydroxymethyl cytosine (5hmC), which is abundant in the brain (Tognini et al. 2015). The appropriate balance between methylated and demethylated states defines the state of health and disease.
The Epigenetic Role of Vitamin C in Neurological Development and Disease
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Cellular systems must translate a barrage of extracellular stimuli into functional changes in gene expression to survive and respond appropriately to environmental challenges. The epigenetic landscape serves to interpret these complex extracellular cues and coordinate a pertinent response by regulating relevant expression of the genome. Methylation at the C5 position of cytosine (5-methylcytosine [5mC]) is the most prevalent epigenetic modification in vertebrates and plays essential roles in development, in transcriptional regulation, and in governing cell identity [1]. These processes are facilitated by methyl-CpG-binding proteins that recognize 5mC and regulate the transcription of methylated genomic loci. The 5mC is considered a stable epigenetic hallmark of DNA and is maintained upon DNA replication by DNA methyltransferase 1 (DNMT1). Therefore, it was long believed that due to proper DNMT1 maintenance, 5mC was a permanent modification in the genome [2]. However, this poses a problem to the cell: How can the cell respond to dynamic environmental stimuli if its most prevalent epigenetic modification is irreversible? It was thus reasoned that there must be a process by which to remove this mark.
The Molecular Genetics OF DNA Methylation in Colorectal Cancer
Published in Leonard H. Augenlicht, Cell and Molecular Biology of Colon Cancer, 2019
How could the alterations in genomic 5-methylcytosine in human premalignant and malignant neoplasms arise, and how might these alterations play a causal role in human carcinogenesis? There are at least five possible explanations. First, it could arise from a defect in maintenance methylation, as originally proposed by Holliday.29 Thus integrity of the enzyme responsible for DNA methylation may be impaired in some way, leading to progressive loss of DNA methylation at random sites throughout the genome. This appears to be an unlikely mechanism, for two reasons: (1) if this were the mechanism, then one would expect the alterations to be random, not limited to certain genes, as we have observed; and (2) when the activity of DNA methyltransferase is measured directly, there appears to be a generalized increase in activity.86 Thus, if anything, the normal metabolic machinery for preserving DNA methylation is enhanced in tumor cells, probably in response to a perceived hypomethylation in the cells.
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.
Targeted sequencing approach: Comprehensive analysis of DNA methylation and gene expression across blood and brain regions in suicide victims
Published in The World Journal of Biological Psychiatry, 2023
Katarina Kouter, Tomaž Zupanc, Alja Videtič Paska
DNA methylation is the addition of a single methyl group to a cytosine, leading to formation of 5-methylcytosine (5mC) (Prokhortchouk and Defossez 2008). The reaction is catalysed by enzymes from the DNA methyltransferases (DNMT) family, with the donor of methyl group being S-adenosyl methionine (Lyko 2018). 5mC can usually be found clustered in CpG dinucleotide motifs. CpG clusters form CpG islands (CGI) and act as regulators of gene expression in promoters and first exons (Deaton and Bird 2011). Methylation of a promotor CpG island is often associated with decreased levels of gene expression (Illingworth and Bird 2009). DNA methylation may affect gene expression following two mechanisms. First, addition of a methyl group alters DNA biophysical properties and prevents the binding of transcriptional factors to DNA (Lee et al. 2014). Second, it attracts proteins that bind to methylated DNA and thus prevent gene transcription (Du et al. 2015).
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.