Methylome and epigenetic markers
Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos in New Technologies and Perinatal Medicine, 2019
DNA methylation is mediated by DNA methyl transferases (DNMT), which are enzymes responsible for catalyzing, recognizing, adding, and removing methyl groups. They are separated into two main classes: writers and erasers. Writers catalyze the addition of the methyl group onto cytosine residues, and erasers are associated with methyl group modification and removal. Specifically, DNMT1 is responsible for maintaining the heritable methyl group on the cytosine residues and has a preference for hemimethylated CpG sites generated by DNA replication (5). DNMT3A and DNMT3B are de novo methyltransferases responsible for methylating CpGs missed by DNMT1 (6,7). When DNA demethylation is required, either a passive or an active demethylation process takes place. Passive demethylation involves the inhibition of DNMT1 during cell replication in dividing cells. Active DNA demethylation involves enzymatic reactions to remove the methyl group from the cytosine residues, and it occurs in both dividing and nondividing cells (8). This mechanism allows for the embryonic development by controlling expression of genes at specific times and tissues.
Ascorbate as an Enzyme Cofactor
Qi Chen, Margreet C.M. Vissers in Vitamin C, 2020
The posttranslational modification of collagen by hydroxylation was first described in the 1940s and 1950s [60–64], and the prolyl hydroxylase enzymes responsible were the first identified 2-OGDDs [65–68]. Since this time, the prevalence of protein hydroxylation has become apparent, and this modification is now recognized as being critical to the regulation of the hypoxic response [69–71] and to protein synthesis by modification of ribosomal proteins [57,72]. In addition, demethylation of histones, DNA, and RNA is initiated by oxidative hydroxylation of methyllysine [73–79], methylarginine [80–83], methylcytosine [84,85], and methyladenosine [86–88]. The number of enzymes identified as 2-OGDDs active in mammalian cells has increased rapidly in this century, and their widespread influence on many fundamental aspects of biology is becoming well recognized. Table 5.1 contains a summary of the more than 50 2-OGDD enzymes identified to date in mammalian cells.
Epigenetics
Sara C. Zapico in Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
DNA methylation is a covalent modification of cytosine residues in cytosine/guanine-rich regions, called CpGs islands. These islands are placed in gene regulatory elements like promoters and other genomic sites, such as intergenic regions and repetitive elements (Mehler 2008). Proteins with the Methyl-CpG-binding domain bind specifically to these islands, inducing, generally, transcriptional repression, although activation has also been reported. Enzymes involved in this process are DNA methyltransferases (DNMTs), catalyzing this reaction by transferring methyl groups from S-adenosylmethionine to cytosine residues (Qureshi and Mehler 2011) and Ten-eleven translocator enzymes (TETs), involved in methyl cytosine hydroxylation, which ultimately remove the mark (Bermejo-Alvarez et al. 2015). Demethylation can be achieved passively during DNA replication (Kagiwada et al. 2013), or actively mainly by TET enzymes (Tahiliani et al. 2009).
Mepolizumab for the treatment of eosinophilic granulomatosis with polyangiitis
Published in Expert Opinion on Biological Therapy, 2019
Daniel Ennis, Jason Kihyuk Lee, Christian Pagnoux
The majority of patients in published studies on epigenetic abnormalities in AAV had MPA or GPA, with only a minority classified as EGPA. Epigenetic abnormalities can result in increased mRNA expression of Proteinase 3 (PRTN3) and MPO genes in AAV [59]. During disease activity, decreased expression of euchromatic histone-lysine N-methyltransferase genes (EHMT) 1 and 2 and increased expression of male sex lethal 1 homolog (MSL1) and insulin growth factor (ING4) genes correlated with MPO and PRTN3 expression [60]. Furthermore, demethylation of the PRTN3 promoter region was predictive of disease relapse irrespective of ANCA serotype (HR 4.55) [61]. These advances in our understanding of the contributions of genetic and epigenetic variables to EGPA have not yet identified clinically distinct subgroups to guide therapy.
Early-life adversity-induced long-term epigenetic programming associated with early onset of chronic physical aggression: Studies in humans and animals
Published in The World Journal of Biological Psychiatry, 2019
Dimitry A. Chistiakov, Vladimir P. Chekhonin
DNA methyltransferases (DNMTs) are involved in cytosine methylation using S-adenosyl methionine as the methyl donor. In mammals, DNMT1 is the most abundant DNA methyltransferase that plays a key role in maintenance of genome-wide methylation patterns. This enzyme is more active on hemimethylated DNA than on unmethylated CpG dinucleotides and therefore preferentially methylates hemimethylated substrates (Mohan & Chaillet 2013). In contrast, DNMT3 acts on unmethylated and hemimethylated DNA at equal rates. DNMT3a, DNMT3b and DNMT3L comprise a family of DNMT3 methylases. DNMT3a and DNMT3b are implicated in de novo DNA methylation (Okano et al. 1999). DNMT3L lacks methyltransferase activity but is essential for the establishment of maternal methylation imprints and appropriate (allele-specific) expression of maternally imprinted genes (Hata et al. 2002). DNA demethylation is performed through complex DNA excision/repair-based mechanisms involving oxidation of the methyl group by TET dioxygenases and further restoration of intact cytosines (Wu & Zhang 2014). 5-Hydroxymethylcytosine may be reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair (Kohli & Zhang 2013). However, conversion of 5-hydroxymethylcytosine to cytosine is not completely resolved so far.
Emerging DNA methylation inhibitors for cancer therapy: challenges and prospects
Published in Expert Review of Precision Medicine and Drug Development, 2019
Aurora Gonzalez-Fierro, Alfonso Dueñas-González
Since DNA methylation is dynamic, mammalian cells also possess the ability to remove these marks. Passive DNA demethylation was the first to be described. As it is passive, it depends on DNA replication and cell division plus the subsequent lack of action of DNA methylation maintenance pathways. On the contrary, active DNA demethylation is replication-independent and occurs through the active enzymatic removal of the methylcytosine [27]. Among DNA demethylases, the enzyme activation-induced cytidine deaminase (AID) deaminate 5-mC yielding thymidine that is replaced by an unmethylated cytosine by the base-excision repair (BER) pathway. Thus, AID may promote aberrant gene expression by decreasing the promoter DNA methylation of specific genes [28,29]. The family of tet1, tet2, and tet3 (ten-eleven translocation) proteins are also considered active DNA demethylases. These enzymes carry out the hydroxylation of 5-mC to 5-hmC [30], 5-hmC, in turn, is replaced with an unmethylated cytosine by the BER pathway [31]. Recent data demonstrate that several proteins bind to 5-hmC, revealing the possibility that specific proteins may be able to interpret the 5-hmC epigenetic mark and subsequently influence chromatin structure and gene expression [32,33]. Taken together, the establishment and maintenance model of DNA methylation is likely an oversimplification of what actually occurs and all DNMTs in concert with tet enzymes, regulate DNA methylation levels through a dynamic equilibrium of site-specific gain and loss of methylation during development and health and disease conditions.
Related Knowledge Centers
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