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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.
Toxicogenomics
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Anirudh J. Chintalapati, Zacharoula Konsoula, Barile Frank A.
DNA methylation has long been regarded as an epigenetic silencing mechanism of cardinal significance in transcription, chromatin structure, genomic imprinting, and chromosome instability. Modification by DNA methylation arises by the covalent attachment of a methyl group to position 5 of the cytosine ring, forming 5-methylcytosine. DNA methylation induces transcription, in which the methyl group that extends out from the cytosine nucleotide substitutes for transcription factors that commonly attach to the DNA, or entices methyl-binding domains, which in turn are implicated in gene suppression and chromatin condensation. DNA methyl transferases (DNMTs) are the enzymes that catalyze this reaction by substituting the hydrogen with a methyl group on position 5 of the pyrimidine ring in the cytosine molecule. DNMT1, DNMT2, DNMT3a, and DNMT3b are the most commonly recognized mammalian DNA methyltransferases; hemimethylated DNA is the target of DNMT1 (maintenance methylation), and DNMT3a and 3b are responsible for de novo methylation. Biochemical analyses of DNMT2 enzymes that contain motifs similar to DNA methyltransferases demonstrated very weak, albeit no specific, DNA methyltransferase activity. However, recent studies confirm RNA methylation activity of DNMT2 at cytosine38 (C38) of tRNAAspGTC in mice, Drosophila melanogaster, and Arabidopsis thaliana. Furthermore, sequence alignment analysis of methyltransferase catalytic domains suggests that eukaryotic DNMT1, DNMT2, and DNMT3 probably evolved from common ancestral DNMT2-like RNA methyltransferases.
Investigation of DNA Methylation in Autosomal Dominant Polycystic Kidney Disease
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
DNA methylation is catalyzed by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3a, DNMT3b, and DNMT3L,21,22 which differ in structure and function. Apart from DNMT2, which has very weak activity toward DNA methylation,24 all DNMTs comprise a C-terminal catalytic domain and an N-terminal regulatory domain. DNMT3a and DNMT3b are extremely similar in structure and function, capable of methylating both naked and hemi-methylated DNA. For this reason, they are referred to as de novo DNMTs. Localized at the replication fork, the ubiquitously expressed DNMT1 displays a preference for hemi-methylated DNA, copying methylation patterns from parental DNA established by the DNMT3 family (DNMT 3a and DNMT 3b) onto newly synthesized DNA during DNA replication21,22 and DNA repair.25 As such, DNMT1 functions to maintain DNA methylation in our genome. Like DNMT1, DNMT3a is also ubiquitously expressed and mice lacking DNMT3a die at about 4 weeks of age. DNMT3b on the other hand is poorly expressed in the majority of differentiated tissues26 and knockout of DNMT3b induces embryonic lethality.27 These animal studies suggest that DNMT3a is required for normal cellular differentiation, while DNMT3b is required during early development. The final member of the DNMT family, DNMT3L, lacks the catalytic domain present in the other enzymes. However, it acts as a cofactor to DNMT3a and DNMT3b.28–30 Mouse studies show that DNMT3L is expressed during gametogenesis and is required for the establishment of maternal genomic imprinting31,32 and mice lacking DNMT3L die early during development.32
Epigenetic aspects of multiple sclerosis and future therapeutic options
Published in International Journal of Neuroscience, 2021
Khosro Jamebozorgi, Daryoush Rostami, Hosein Pormasoumi, Eskandar Taghizadeh, George E. Barreto, Amirhossein Sahebkar
DNA methylation is a well-studied epigenetic mechanism in MS patients [35–37]. There are several DNA methyltransferase (DNMT) enzymes, whose role is toadd the methyl group to carbon 5 cytosine in DNA. These enzymes are categorized into two groups, maintenance DNMTs (DNMT1 and DNMT2) and de novo DNMTs (DNMT3a, DNMT3b, and DNMT3L) (Figure 2) [7,38]. DNMT1, present in the replication fork accompanied with DNMT2, is responsible for maintaining the methylation patterns during replication and methylate’s nascent DNA strand; on the contrary, DNMT3a, DNMT3L and DNMT3b are responsible for de novo methylation in sites of non-methylated or hemi-methylated DNA . DNMT3a is involved in the methylation of nuclear DNA while DNMT3b is responsible for de novo methylation of mitochondrial DNA [7,39]. DNA methylation compresses the structure of chromatin; in contrast, non-methylated DNA has a euchromatin structure, where transcription factors interact to and enhance or inhibit gene expression [7,40,41]. The CpG sites with cytosine and guanine nucleotides, which are frequently found in gene promoter regions, are places in the DNA that are methylated in mammals [34]. Other sites in DNA involved in methylation are repetitive sequences and CpG island shores located up to 2 Kb from CpG islands [42,43]. Hypermethylation of CpG sites in promoter region prevents the expression of related genes and this mechanism can be associated with MS pathogenesis. However, patterns of methylation might be different and depend on the genomic context [34].
Circulating extracellular vesicle content reveals de novo DNA methyltransferase expression as a molecular method to predict septic shock
Published in Journal of Extracellular Vesicles, 2019
Duaa A. Dakhlallah, Jon Wisler, Marieta Gencheva, Candice M. Brown, Erin R. Leatherman, Kanhaiya Singh, Kathy Brundage, Todd Karsies, Ahmad Dakhlallah, Kenneth W. Witwer, Chandan K. Sen, Timothy D. Eubank, Clay B. Marsh
DNA methylation is a heritable epigenetic marker where DNA methyltransferases (DNMTs) covalently transfer methyl groups to the C-5 position in the cytosine ring [1,2]. DNA methylation occurs enzymatically at gene promoters to serve as a transcriptional OFF switch. In general, this epigenetic modification can establish a unique pattern of transcriptional suppression that can lead to permanent gene silencing [3]. Distinct DNMTs exist to maintain pre-existing methylation patterns [4], as well as initiate alternative methylation signatures during disease development [2]. Currently, there are five known mammalian DNMTs: DNMT1, DNMT3A, DNMT3B [5], DNMT2, and DNMT3L. DNMT1 recognizes hemi-methylated DNA and maintains parent DNA methylation patterns during DNA replication, while DNMT3A and DNMT3B establish de novo DNA methylation. These distinct epigenetic functions between DNMT types are not exclusive and can overlap [1]. DNMT2 is a transfer RNA methyltransferase for cytosine-5 methylation with very low DNA methylation catalytic activity [6]. DNMT3L lacks enzymatic activity but can interact with DNMT3A/3B and other repressor complexes to set up methylation imprints during gametogenesis [7].
Prognostic value of DNMT3A mutations in myelodysplastic syndromes: a meta-analysis
Published in Hematology, 2019
Simin Liang, Xiaojia Zhou, Hui Pan, Yichun Yang, Lin Shi, Li Wang
Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal diseases originated from hematopoietic stem cells, which are characterized by cytopenia, ineffective hematopoiesis, hematopoietic failure and high-risk transformation to acute myeloid leukemia (AML) [1]. With the development of gene sequencing technology, an increasing number of somatic mutant genes have been detected in MDS. DNMT3A is one of the most common mutated genes found in MDS patients [2,3], belonging to DNA methyltransferase (DNMT) family. There are mainly three functional DNA methyltransferases in mammals: DNMT1, DNMT3A, DNMT3B [4]. DNMT1 is a maintenance methylase [5], by the way, DNMT2 is not a DNA methyltransferase. DNMT3A gene is encoded by 23 exons on human chromosome 2p23, and encodes a 908-amino acid protein that, along with DNMT3B, is responsible for de novo CpG methylation independent of replication [6,7].