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Exercise, Metabolism and Oxidative Stress in the Epigenetic Landscape
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Gareth W. Davison, Colum P. Walsh
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).
Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
The activity associated with DNA methyltransferase displays its remarkable benchmark role in the malignant growth of tumor cells. In addition, the activity of HMNT inhibitors might be easily analyzed. Various histone methyltransferase inhibitors have been highly developed from natural resources as potential therapeutic cancer agents.
Effects of Air Pollution on Allergy and Asthma
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Pollutants can affect the lung by altering its immune response and airway inflammation. Susceptibility to air pollutants differs among individuals, as exemplified by several diseases and conditions (e.g., asthma) in which both genetic and non-genetic factors seem to play a role in the individual response to ambient air pollution. In general, DNA methyltransferases are responsible for maintaining the methylation pattern from parental to daughter DNA strands upon cell division, and most cells have their epigenetic marks fixed when they differentiate or exit the cell cycle. However, in certain situations such as disease, or in normal development, these epigenetic marks are removed and re-established in a process called ‘reprogramming’. Of all the epigenetic modifications mentioned above, DNA methylation holds a higher potential of being transmitted through generations, despite the reprogramming events mentioned.
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.
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.
Do histone deacytelase inhibitors and azacitidine combination hold potential as an effective treatment for high/very-high risk myelodysplastic syndromes?
Published in Expert Opinion on Investigational Drugs, 2021
Hypermethylation of the promoters of the tumor suppressor genes resulting in epigenetic silencing, results in pathogenicity of several hematological malignancies[13]. Azacitidine is a pyrimidine nucleoside analog of cytidine that is phosphorylated intracellularly to its active form, azacitidine triphosphate[14]. The anti-tumor activity of azacitidine is by DNA hypomethylation and a cytotoxic effect on defective hematopoietic cells in the bone marrow. Azacitidine inhibits DNA methyltransferase activity and methylation of the DNA. In vivo reduction in global DNA methylation was observed in hematological malignancies, whether AZA was administered intravenously or subcutaneously[14]. DNA hypomethylation may result in re-activation of silenced genes with restoration of cancer-suppressing function and cellular differentiation. In pivotal clinical studies, therapy with AZA resulted in reduction in DNA methylation in patients with MDS/acute myeloid leukemia (AML)[15]. This results in restoration of function of tumor suppressor gene and cellular differentiation. However, in vitro studies suggest that DNA hypomethylation of gene promoters may not completely explain gene reactivation[16].