Journal articles: 'DNMT2'

1

MUND, Cora, Tanja MUSCH, Martin STRÖDICKE, Birte ASSMANN, En LI, and Frank LYKO. "Comparative analysis of DNA methylation patterns in transgenic Drosophila overexpressing mouse DNA methyltransferases." Biochemical Journal 378, no. 3 (March 15, 2004): 763–68. http://dx.doi.org/10.1042/bj20031567.

Full text

Abstract:

DNA methyltransferases (Dnmts) mediate the epigenetic modification of eukaryotic genomes. Mammalian DNA methylation patterns are established and maintained by co-operative interactions among the Dnmt proteins Dnmt1, Dnmt3a and Dnmt3b. Owing to their simultaneous presence in mammalian cells, the activities of individual Dnmt have not yet been determined. This includes a fourth putative Dnmt, namely Dnmt2, which has failed to reveal any activity in previous assays. We have now established transgenic Drosophila strains that allow for individual overexpression of all known mouse Dnmts. Quantitative analysis of genomic cytosine methylation levels demonstrated a robust Dnmt activity for the de novo methyltransferases Dnmt3a and Dnmt3b. In addition, we also detected a weak but significant activity for Dnmt2. Subsequent methylation tract analysis by genomic bisulphite sequencing revealed that Dnmt3 enzymes preferentially methylated CpG dinucleotides in a processive manner, whereas Dnmt2 methylated isolated cytosine residues in a non-CpG dinucleotide context. Our results allow a direct comparison of the activities of mammalian Dnmts and suggest a significant functional specialization of these enzymes.

APA, Harvard, Vancouver, ISO, and other styles

2

Liu, Kui, Yun Fei Wang, Carmen Cantemir, and Mark T. Muller. "Endogenous Assays of DNA Methyltransferases: Evidence for Differential Activities of DNMT1, DNMT2, and DNMT3 in Mammalian Cells In Vivo." Molecular and Cellular Biology 23, no. 8 (April 15, 2003): 2709–19. http://dx.doi.org/10.1128/mcb.23.8.2709-2719.2003.

Full text

Abstract:

ABSTRACT While CpG methylation can be readily analyzed at the DNA sequence level in wild-type and mutant cells, the actual DNA (cytosine-5) methyltransferases (DNMTs) responsible for in vivo methylation on genomic DNA are less tractable. We used an antibody-based method to identify specific endogenous DNMTs (DNMT1, DNMT1b, DNMT2, DNMT3a, and DNMT3b) that stably and selectively bind to genomic DNA containing 5-aza-2′-deoxycytidine (aza-dC) in vivo. Selective binding to aza-dC-containing DNA suggests that the engaged DNMT is catalytically active in the cell. DNMT1b is a splice variant of the predominant maintenance activity DNMT1, while DNMT2 is a well-conserved protein with homologs in plants, yeast, Drosophila, humans, and mice. Despite the presence of motifs essential for transmethylation activity, catalytic activity of DNMT2 has never been reported. The data here suggest that DNMT2 is active in vivo when the endogenous genome is the target, both in human and mouse cell lines. We quantified relative global genomic activity of DNMT1, -2, -3a, and -3b in a mouse teratocarcinoma cell line. DNMT1 and -3b displayed the greatest in vivo binding avidity for aza-dC-containing genomic DNA in these cells. This study demonstrates that individual DNMTs can be tracked and that their binding to genomic DNA can be quantified in mammalian cells in vivo. The different DNMTs display a wide spectrum of genomic DNA-directed activity. The use of an antibody-based tracking method will allow specific DNMTs and their DNA targets to be recovered and analyzed in a physiological setting in chromatin.

APA, Harvard, Vancouver, ISO, and other styles

3

Del Castillo Falconi, Victor M., Karla Torres-Arciga, Genaro Matus-Ortega, José Díaz-Chávez, and Luis A. Herrera. "DNA Methyltransferases: From Evolution to Clinical Applications." International Journal of Molecular Sciences 23, no. 16 (August 12, 2022): 8994. http://dx.doi.org/10.3390/ijms23168994.

Full text

Abstract:

DNA methylation is an epigenetic mark that living beings have used in different environments. The MTases family catalyzes DNA methylation. This process is conserved from archaea to eukaryotes, from fertilization to every stage of development, and from the early stages of cancer to metastasis. The family of DNMTs has been classified into DNMT1, DNMT2, and DNMT3. Each DNMT has been duplicated or deleted, having consequences on DNMT structure and cellular function, resulting in a conserved evolutionary reaction of DNA methylation. DNMTs are conserved in the five kingdoms of life: bacteria, protists, fungi, plants, and animals. The importance of DNMTs in whether methylate or not has a historical adaptation that in mammals has been discovered in complex regulatory mechanisms to develop another padlock to genomic insurance stability. The regulatory mechanisms that control DNMTs expression are involved in a diversity of cell phenotypes and are associated with pathologies transcription deregulation. This work focused on DNA methyltransferases, their biology, functions, and new inhibitory mechanisms reported. We also discuss different approaches to inhibit DNMTs, the use of non-coding RNAs and nucleoside chemical compounds in recent studies, and their importance in biological, clinical, and industry research.

APA, Harvard, Vancouver, ISO, and other styles

4

KIM, SEON-HEE, HYE-JEONG CHO, WOON-MOK SOHN, CHUN-SEOB AHN, YOON KONG, HYUN-JONG YANG, and YOUNG-AN BAE. "Egg-specific expression of protein with DNA methyltransferase activity in the biocarcinogenic liver fluke Clonorchis sinensis." Parasitology 142, no. 9 (June 3, 2015): 1228–38. http://dx.doi.org/10.1017/s0031182015000566.

Full text

Abstract:

SUMMARYDespite recent reports regarding the biology of cytosine methylation in Schistosoma mansoni, the impact of the regulatory machinery remains unclear in diverse platyhelminthes. This ambiguity is reinforced by discoveries of DNA methyltransferase 2 (DNMT2)-only organisms and the substrate specificity of DNMT2 preferential to RNA molecules. Here, we characterized a novel DNA methyltransferase, named CsDNMT2, in a liver fluke Clonorchis sinensis. The protein exhibited structural properties conserved in other members of the DNMT2 family. The native and recombinant CsDNMT2 exhibited considerable enzymatic activity on DNA. The spatiotemporal expression of CsDNMT2 mirrored that of 5-methylcytosine (5 mC), both of which were elevated in the C. sinensis eggs. However, CsDNMT2 and 5 mC were marginally detected in other histological regions of C. sinensis adults including ovaries and seminal receptacle. The methylation site seemed not related to genomic loci occupied by progenies of an active long-terminal-repeat retrotransposon. Taken together, our data strongly suggest that C. sinensis has preserved the functional DNA methylation machinery and that DNMT2 acts as a genuine alternative to DNMT1/DNMT3 to methylate DNA in the DNMT2-only organism. The epigenetic regulation would target functional genes primarily involved in the formation and/or maturation of eggs, rather than retrotransposons.

APA, Harvard, Vancouver, ISO, and other styles

5

Zhu, Huolan, Xiang Wang, Xuyang Meng, Yiya Kong, Yi Li, Chenguang Yang, Ying Guo, et al. "Selenium Supplementation Improved Cardiac Functions by Suppressing DNMT2-Mediated GPX1 Promoter DNA Methylation in AGE-Induced Heart Failure." Oxidative Medicine and Cellular Longevity 2022 (April 6, 2022): 1–12. http://dx.doi.org/10.1155/2022/5402997.

Full text

Abstract:

Objective. Advanced glycation end products (AGEs) are featured metabolites associated with diabetic cardiomyopathy which is characterized by heart failure caused by myocyte apoptosis. Selenium was proved cardioprotective. This study was aimed at investigating the therapeutic effects and underlying mechanisms of selenium supplementation on AGE-induced heart failure. Methods. Rats and primary myocytes were exposed to AGEs. Selenium supplementation was administrated. Cardiac functions and myocyte apoptosis were evaluated. Oxidative stress was assessed by total antioxidant capacity (TAC), reactive oxygen species (ROS) generation, and GPX activity. Expression levels of DNA methyltransferases (DNMTs) and glutathione peroxidase 1 (GPX1) were evaluated. DNA methylation of the GPX1 promoter was analyzed. Results. AGE exposure elevated intracellular ROS generation, induced myocyte apoptosis, and impaired cardiac functions. AGE exposure increased DNMT1 and DNMT2 expression, leading to the reduction of GPX1 expression and activity in the heart. Selenium supplementation decreased DNMT2 expression, recovered GPX1 expression and activity, and alleviated intracellular ROS generation and myocyte apoptosis, resulting in cardiac function recovery. DNA methylation analysis in primary myocytes indicated that selenium supplementation or DNMT inhibitor AZA treatment reduced DNA methylation of the GPX1 gene promoter. Selenium supplementation and AZA administration showed synergic inhibitory effect on GPX1 gene promoter methylation. Conclusions. Selenium supplementation showed cardioprotective effects on AGE-induced heart failure by suppressing ROS-mediated myocyte apoptosis. Selenium supplementation suppressed ROS generation by increasing GPX1 expression via inhibiting DNMT2-induced GPX1 gene promoter DNA methylation in myocytes exposed to AGEs.

APA, Harvard, Vancouver, ISO, and other styles

6

Vivekanandan, Perumal, Hubert Darius-J. Daniel, Rajesh Kannangai, Francisco Martinez-Murillo, and Michael Torbenson. "Hepatitis B Virus Replication Induces Methylation of both Host and Viral DNA." Journal of Virology 84, no. 9 (February 10, 2010): 4321–29. http://dx.doi.org/10.1128/jvi.02280-09.

Full text

Abstract:

ABSTRACT Control of viral replication is a major therapeutic goal to reduce morbidity and mortality from chronic hepatitis B virus (HBV) infection. Recently, methylation has been identified as a novel host defense mechanism, and methylation of viral DNA leads to downregulation of HBV gene expression. To better understand the mechanisms of HBV methylation, cell lines were exposed to HBV using a model system that mimics natural infection and the expression of host DNA methyltransferase genes (DNMTs) was measured. DNMT1, DNMT2, and DNMT3 were all significantly upregulated in response to HBV. DNMT3 was further studied because of its known role in the de novo methylation of DNA. Cotransfection experiments with full-length HBV and DNMT3 led to the downregulation of viral protein and pregenomic RNA production. To investigate whether the upregulation of DNMTs could also have an effect on the methylation of host DNA, cell lines were exposed to HBV in two independent model systems, one that mimics natural infection and a second model with temporary transfection. Host DNA methylation was measured by DNA microarray analysis. Increased methylation of host CpG islands was detected in both experimental systems. Two CpG islands, corresponding to genes SUFU and TIRAP, were selected, and the downregulation of these genes in hepatocellular carcinomas was confirmed. In conclusion, hepatocytes respond to HBV infection by upregulating DNMTs. The DNMTs methylate viral DNA, leading to decreased viral gene expression and decreased viral replication. However, virus-induced overexpression of DNMTs also leads to methylation of host CpG islands.

APA, Harvard, Vancouver, ISO, and other styles

7

Huang, Zhi-Xuan, Jing Li, Qing-Ping Xiong, Hao Li, En-Duo Wang, and Ru-Juan Liu. "Position 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2." Nucleic Acids Research 49, no. 22 (December 6, 2021): 13045–61. http://dx.doi.org/10.1093/nar/gkab1148.

Full text

Abstract:

Abstract Dnmt2, a member of the DNA methyltransferase superfamily, catalyzes the formation of 5-methylcytosine at position 38 in the anticodon loop of tRNAs. Dnmt2 regulates many cellular biological processes, especially the production of tRNA-derived fragments and intergenerational transmission of paternal metabolic disorders to offspring. Moreover, Dnmt2 is closely related to human cancers. The tRNA substrates of mammalian Dnmt2s are mainly detected using bisulfite sequencing; however, we lack supporting biochemical data concerning their substrate specificity or recognition mechanism. Here, we deciphered the tRNA substrates of human DNMT2 (hDNMT2) as tRNAAsp(GUC), tRNAGly(GCC) and tRNAVal(AAC). Intriguingly, for tRNAAsp(GUC) and tRNAGly(GCC), G34 is the discriminator element; whereas for tRNAVal(AAC), the inosine modification at position 34 (I34), which is formed by the ADAT2/3 complex, is the prerequisite for hDNMT2 recognition. We showed that the C32U33(G/I)34N35 (C/U)36A37C38 motif in the anticodon loop, U11:A24 in the D stem, and the correct size of the variable loop are required for Dnmt2 recognition of substrate tRNAs. Furthermore, mammalian Dnmt2s possess a conserved tRNA recognition mechanism.

APA, Harvard, Vancouver, ISO, and other styles

8

Lyko, Frank. "RNA Methylation and Its Role in the Hematopoietic System." Blood 130, Suppl_1 (December 7, 2017): SCI—52—SCI—52. http://dx.doi.org/10.1182/blood.v130.suppl_1.sci-52.sci-52.

Full text

Abstract:

Abstract RNA methylation represents a novel expansion of traditional epigenetic concepts. RNAs can be methylated at adenine and at cytosine residues, and both modifications have distinct regulatory potential. Our work focuses on the DNMT2 enzyme, which is a member of the animal (cytosine-5) DNA methyltransferase family and has long been considered to function as a DNA methyltransferase. However, a DNA methyltransferase activity could not be confirmed conclusively and more recent work clearly demonstrates that DNMT2 is a tRNA methyltransferase. This unexpected substrate is interpreted to reflect an evolutionary ancient substrate switch from DNA to tRNA that expanded the epigenetic regulatory capacity of the DNMT family to also include RNA. To analyze the function of DNMT2, we performed a detailed analysis of knockout mice. These mice are viable and fertile, but also show a reduction of hematopoietic stem and progenitor cell populations and a cell-autonomous defect in their differentiation.1 RNA bisulfite sequencing revealed that Dnmt2 methylates C38 of tRNA Asp(GTC), Gly(GCC), and Val(AAC). Proteomic analyses from primary bone marrow cells uncovered systematic differences in protein expression that are due to specific codon mistranslation by tRNAs lacking DNMT2-dependent methylation. Together, these results illustrate the regulatory capacity of DNMT2-mediated tRNA methylation in genome recoding.2 Our current work addresses additional mechanistic aspects that link tRNA methylation to translational fidelity and investigates the relevance of DNMT2-mediated tRNA methylation for leukemogenesis. 1. Tuorto F, Herbst F, Alerasool N, et al. The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis. EMBO J. 2015;34(18):2350-2362. 2. Tuorto F, Lyko F. Genome recoding by tRNA modifications. Open Biol. 2016;6(12):160287. Disclosures No relevant conflicts of interest to declare.

APA, Harvard, Vancouver, ISO, and other styles

9

Goll, Mary Grace, Finn Kirpekar, Keith A. Maggert, Jeffrey A. Yoder, Chih-Lin Hsieh, Xiaoyu Zhang, Kent G. Golic, Steven E. Jacobsen, and Timothy H. Bestor. "Methylation of tRNAAsp by the DNA Methyltransferase Homolog Dnmt2." Science 311, no. 5759 (January 20, 2006): 395–98. http://dx.doi.org/10.1126/science.1120976.

Full text

Abstract:

The sequence and the structure of DNA methyltransferase-2 (Dnmt2) bear close affinities to authentic DNA cytosine methyltransferases. A combined genetic and biochemical approach revealed that human DNMT2 did not methylate DNA but instead methylated a small RNA; mass spectrometry showed that this RNA is aspartic acid transfer RNA (tRNAAsp) and that DNMT2 specifically methylated cytosine 38 in the anticodon loop. The function of DNMT2 is highly conserved, and human DNMT2 protein restored methylation in vitro to tRNAAsp from Dnmt2-deficient strains of mouse, Arabidopsis thaliana, and Drosophila melanogaster in a manner that was dependent on preexisting patterns of modified nucleosides. Indirect sequence recognition is also a feature of eukaryotic DNA methyltransferases, which may have arisen from a Dnmt2-like RNA methyltransferase.

APA, Harvard, Vancouver, ISO, and other styles

10

Bhattacharya, Tamanash, Danny W. Rice, John M. Crawford, Richard W. Hardy, and Irene L. G. Newton. "Evidence of Adaptive Evolution in Wolbachia-Regulated Gene DNMT2 and Its Role in the Dipteran Immune Response and Pathogen Blocking." Viruses 13, no. 8 (July 27, 2021): 1464. http://dx.doi.org/10.3390/v13081464.

Full text

Abstract:

Eukaryotic nucleic acid methyltransferase (MTase) proteins are essential mediators of epigenetic and epitranscriptomic regulation. DNMT2 belongs to a large, conserved family of DNA MTases found in many organisms, including holometabolous insects such as fruit flies and mosquitoes, where it is the lone MTase. Interestingly, despite its nomenclature, DNMT2 is not a DNA MTase, but instead targets and methylates RNA species. A growing body of literature suggests that DNMT2 mediates the host immune response against a wide range of pathogens, including RNA viruses. Curiously, although DNMT2 is antiviral in Drosophila, its expression promotes virus replication in mosquito species. We, therefore, sought to understand the divergent regulation, function, and evolution of these orthologs. We describe the role of the Drosophila-specific host protein IPOD in regulating the expression and function of fruit fly DNMT2. Heterologous expression of these orthologs suggests that DNMT2′s role as an antiviral is host-dependent, indicating a requirement for additional host-specific factors. Finally, we identify and describe potential evidence of positive selection at different times throughout DNMT2 evolution within dipteran insects. We identify specific codons within each ortholog that are under positive selection and find that they are restricted to four distinct protein domains, which likely influence substrate binding, target recognition, and adaptation of unique intermolecular interactions. Collectively, our findings highlight the evolution of DNMT2 in Dipteran insects and point to structural, regulatory, and functional differences between mosquito and fruit fly homologs.

APA, Harvard, Vancouver, ISO, and other styles

11

Dev, Rachana Roshan, Rakesh Ganji, Satya Prakash Singh, Sundarasamy Mahalingam, Sharmistha Banerjee, and Sanjeev Khosla. "Cytosine methylation by DNMT2 facilitates stability and survival of HIV-1 RNA in the host cell during infection." Biochemical Journal 474, no. 12 (June 6, 2017): 2009–26. http://dx.doi.org/10.1042/bcj20170258.

Full text

Abstract:

The enigmatic methyltransferase, DNMT2 (DNA methyltransferase 2), structurally resembles a DNA methyltransferase, but has been shown to be a tRNA methyltransferase targeting cytosine within a specific CpG in different tRNA molecules. We had previously shown that, during environmental stress conditions, DNMT2 is re-localized from the nucleus to the cytoplasmic stress granules (SGs) and is associated with RNA-processing proteins. In the present study, we show that DNMT2 binds and methylates various mRNA species in a sequence-independent manner and gets re-localized to SGs in a phosphorylation-dependent manner. Importantly, our results indicate that HIV-1 enhances its survivability in the host cell by utilizing this RNA methylation capability of DNMT2 to increase the stability of its own genome. Upon infection, DNMT2 re-localizes from the nucleus to the SGs and methylates HIV-1 RNA. This DNMT2-dependent methylation provided post-transcriptional stability to the HIV-1 RNA. Furthermore, DNMT2 overexpression increased the HIV-1 viral titre. This would suggest that HIV hijacks the RNA-processing machinery within the SGs to ensure its own survival in the host cell. Thus, our findings provide for a novel mechanism by which virus tries to modulate the host cell machinery to its own advantage.

APA, Harvard, Vancouver, ISO, and other styles

12

Bhattacharya, Tamanash, Liewei Yan, John M. Crawford, Hani Zaher, Irene L. G. Newton, and Richard W. Hardy. "Differential viral RNA methylation contributes to pathogen blocking in Wolbachia-colonized arthropods." PLOS Pathogens 18, no. 3 (March 16, 2022): e1010393. http://dx.doi.org/10.1371/journal.ppat.1010393.

Full text

Abstract:

Arthropod endosymbiont Wolbachia pipientis is part of a global biocontrol strategy to reduce the replication of mosquito-borne RNA viruses such as alphaviruses. We previously demonstrated the importance of a host cytosine methyltransferase, DNMT2, in Drosophila and viral RNA as a cellular target during pathogen-blocking. Here we report a role for DNMT2 in Wolbachia-induced alphavirus inhibition in Aedes species. Expression of DNMT2 in mosquito tissues, including the salivary glands, is elevated upon virus infection. Notably, this is suppressed in Wolbachia-colonized animals, coincident with reduced virus replication and decreased infectivity of progeny virus. Ectopic expression of DNMT2 in cultured Aedes cells is proviral, increasing progeny virus infectivity, and this effect of DNMT2 on virus replication and infectivity is dependent on its methyltransferase activity. Finally, examining the effects of Wolbachia on modifications of viral RNA by LC-MS show a decrease in the amount of 5-methylcytosine modification consistent with the down-regulation of DNMT2 in Wolbachia colonized mosquito cells and animals. Collectively, our findings support the conclusion that disruption of 5-methylcytosine modification of viral RNA is a vital mechanism operative in pathogen blocking. These data also emphasize the essential role of epitranscriptomic modifications in regulating fundamental alphavirus replication and transmission processes.

APA, Harvard, Vancouver, ISO, and other styles

13

Schaefer, Matthias, and Frank Lyko. "Solving the Dnmt2 enigma." Chromosoma 119, no. 1 (September 3, 2009): 35–40. http://dx.doi.org/10.1007/s00412-009-0240-6.

Full text

APA, Harvard, Vancouver, ISO, and other styles

14

Yu, Tian, Yeming Xie, Chong Tang, Yue Wang, Shuiqiao Yuan, Huili Zheng, and Wei Yan. "Dnmt2-null sperm block maternal transmission of a paramutant phenotype†." Biology of Reproduction 105, no. 3 (April 30, 2021): 603–12. http://dx.doi.org/10.1093/biolre/ioab086.

Full text

Abstract:

Abstract Previous studies have shown that Dnmt2-null sperm block the paternal transmission (through sperm) of certain acquired traits, e.g., high-fat diet–induced metabolic disorders or white tails due to a Kit paramutation. Here, we report that DNMT2 is also required for the transmission of a Kit paramutant phenotype (white tail tip) through the female germline (i.e., oocytes). Specifically, ablation of Dnmt2 led to aberrant profiles of tRNA-derived small RNAs (tsRNAs) and other small noncoding RNAs (sncRNAs) in sperm, which correlate with altered mRNA transcriptomes in pronuclear zygotes derived from wild-type oocytes carrying the Kit paramutation and a complete blockage of transmission of the paramutant phenotype through oocytes. Together, the present study suggests that both paternal and maternal transmissions of epigenetic phenotypes require intact DNMT2 functions in the male germline.

APA, Harvard, Vancouver, ISO, and other styles

15

Chen, Zhiyuan, and Yi Zhang. "Role of Mammalian DNA Methyltransferases in Development." Annual Review of Biochemistry 89, no. 1 (June 20, 2020): 135–58. http://dx.doi.org/10.1146/annurev-biochem-103019-102815.

Full text

Abstract:

DNA methylation at the 5-position of cytosine (5mC) plays vital roles in mammalian development. DNA methylation is catalyzed by DNA methyltransferases (DNMTs), and the two DNMT families, DNMT3 and DNMT1, are responsible for methylation establishment and maintenance, respectively. Since their discovery, biochemical and structural studies have revealed the key mechanisms underlying how DNMTs catalyze de novo and maintenance DNA methylation. In particular, recent development of low-input genomic and epigenomic technologies has deepened our understanding of DNA methylation regulation in germ lines and early stage embryos. In this review, we first describe the methylation machinery including the DNMTs and their essential cofactors. We then discuss how DNMTs are recruited to or excluded from certain genomic elements. Lastly, we summarize recent understanding of the regulation of DNA methylation dynamics in mammalian germ lines and early embryos with a focus on both mice and humans.

APA, Harvard, Vancouver, ISO, and other styles

16

Wong, Kah Keng, Charles H. Lawrie, and Tina M. Green. "Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia." Biomarker Insights 14 (January 2019): 117727191984645. http://dx.doi.org/10.1177/1177271919846454.

Full text

Abstract:

Epigenetic alteration has been proposed to give rise to numerous classic hallmarks of cancer. Impaired DNA methylation plays a central role in the onset and progression of several types of malignancies, and DNA methylation is mediated by DNA methyltransferases (DNMTs) consisting of DNMT1, DNMT3A, and DNMT3B. DNMTs are frequently implicated in the pathogenesis and aggressiveness of acute myeloid leukaemia (AML) patients. In this review, we describe and discuss the oncogenic roles of DNMT1, DNMT3A, and DNMT3B in AML. The clinical response predictive roles of DNMTs in clinical trials utilising hypomethylating agents (azacitidine and decitabine) in AML patients are presented. Novel hypomethylating agent (guadecitabine) and experimental DNMT inhibitors in AML are also discussed. In summary, hypermethylation of tumour suppressors mediated by DNMT1 or DNMT3B contributes to the progression and severity of AML (except MLL-AF9 and inv(16)(p13;q22) AML for DNMT3B), while mutation affecting DNMT3A represents an early genetic lesion in the pathogenesis of AML. In clinical trials of AML patients, expression of DNMTs is downregulated by hypomethylating agents while the clinical response predictive roles of DNMT biomarkers remain unresolved. Finally, nucleoside hypomethylating agents have continued to show enhanced responses in clinical trials of AML patients, and novel non-nucleoside DNMT inhibitors have demonstrated cytotoxicity against AML cells in pre-clinical settings.

APA, Harvard, Vancouver, ISO, and other styles

17

Ding, Y. B., J. L. He, X. Q. Liu, X. M. Chen, C. L. Long, and Y. X. Wang. "Expression of DNA methyltransferases in the mouse uterus during early pregnancy and susceptibility to dietary folate deficiency." REPRODUCTION 144, no. 1 (July 2012): 91–100. http://dx.doi.org/10.1530/rep-12-0006.

Full text

Abstract:

We have characterized the uterine expression of DNA methyltransferases (DNMTs) during early pregnancy in mice and determined whether a folate-deficient diet (FDD) can affect DNMTs in this context. Within endometrial cells, expressions of DNMT (cytosine-5) 1 (Dnmt1),Dnmt3a, andDnmt3bwere significantly elevated during the prereceptive phase of pregnancy but generally returned to baseline levels during receptive and postimplantation periods. As such, the transcription of DNMT genes is temporally regulated during early pregnancy. When comparisons were made between implantation sites (IS) and inter-IS on day 5 of pregnancy, lower levels ofDnmt3awere detected at IS. Comparisons between IS and inter-IS did not reveal significant expression differences for other DNMT genes. When tissue sections were examined, DNMT3A was specifically lower in the stroma of IS. Reduced DNMT1 and DNMT3B levels were also observed in the luminal and glandular epithelia of IS, whereas no obvious differences in the stroma were detected. In pseudo-pregnant mice subjected to a FDD, levels ofDnmt1andDnmt3a(but notDnmt3b) were significantly upregulated in endometrial tissues, as compared with controls. When tissues from these folate-deficient mice were examined, DNMT1 levels were elevated in both the luminal and glandular epithelia, whereas DNMT3A was upregulated in the luminal epithelium and the stroma. A slight increase in DNMT3B levels was detected in the glandular epithelium. These results indicate that DNMTs may regulate the transcription of endometrial genes associated with embryo implantation and that levels of DNMTs are affected by dietary folate in mice.

APA, Harvard, Vancouver, ISO, and other styles

18

Kapopara, Ravi, S. Prasanth Kumar, S. K. Patel, D. K. Sadhu, Y. T. Jasrai, H. A. Pandya, and R. M. Rawal. "Virtual screening of natural bioactives in combating cancer through epigenetic modulation." South Asian Journal of Experimental Biology 1, no. 5 (December 5, 2011): 12–16. http://dx.doi.org/10.38150/sajeb.1(5).p12-16.

Full text

Abstract:

Epigenetic events are due to altered gene expression without any changes inthe genetic material and characteristic of heritability via cell division. Theimpact of epigenetic control over cancer is one among the thrust area ofresearch in cancer biology. The present study deals about the virtual screeningof plant derived bioactives, directed against the key molecular regulatorsof the epigenetic eventsÃ‚Â viz. DNA methyltransferases (DNMT1, DNMT2 andDNMT3B), Histone acetyltransferase (HAT), Histone deacetylase 8 (HDAC8),Histone H3 lysine 27 methyl transferase (H3K27MT) and Histone H3 specificlysine 4 demethylase (H3K4DM). This computational screening identifies themost efficient binders with respect to individual targets in terms of ligandbinding energy. The structure optimization of the best scored docked conformationswill be helpful to reveal new insights and development of naturalbioactives to combat cancer.

APA, Harvard, Vancouver, ISO, and other styles

19

Schulz, Eike C., Heide M. Roth, Serge Ankri, and Ralf Ficner. "Structure Analysis of Entamoeba histolytica DNMT2 (EhMeth)." PLoS ONE 7, no. 6 (June 21, 2012): e38728. http://dx.doi.org/10.1371/journal.pone.0038728.

Full text

APA, Harvard, Vancouver, ISO, and other styles

20

Zimmermann, Nicole, Jürgen Zschocke, Tatjana Perisic, Shuang Yu, Florian Holsboer, and Theo Rein. "Antidepressants inhibit DNA methyltransferase 1 through reducing G9a levels." Biochemical Journal 448, no. 1 (October 18, 2012): 93–102. http://dx.doi.org/10.1042/bj20120674.

Full text

Abstract:

The discovery of epigenetic processes as possible pivotal regulatory mechanisms in psychiatric diseases raised the question of how psychoactive drugs may impact the epigenetic machinery. In the present study we set out to explore the specificity and the mode of action of the reported inhibitory effect of the TCA (tricyclic antidepressant) amitriptyline on DNMT (DNA methyltransferase) activity in primary astrocytes from the rat cortex. We found that the impact on DNMT was shared by another TCA, imipramine, and by paroxetine, but not by venlafaxine or the mood stabilizers carbamazepine and valproic acid. DNMT activity in subventricular neural stem cells was refractory to the action of ADs (antidepressants). Among the established DNMTs, ADs primarily targeted DNMT1. The reduction of enzymatic DNMT1 activity was neither due to reduced DNMT1 expression nor due to direct drug interference. We tested putative DNMT1-inhibitory mechanisms and discovered that a known stimulator of DNMT1, the histone methyltransferase G9a, exhibited decreased protein levels and interactions with DNMT1 upon AD exposure. Adding recombinant G9a completely reversed the AD repressive effect on DNMT1 function. In conclusion, the present study presents a model where distinct ADs affect DNMT1 activity via G9a with important repercussions for possible novel treatment regimes.

APA, Harvard, Vancouver, ISO, and other styles

21

Hopfer, Olaf J., Martina Komor, Ina S. Koehler, Matthias Schulze, Claudia Freitag, Dieter Hoelzer, Eckhard Thiel, and Wolf-Karsten Hofmann. "Expression of DNMT Isoforms Is Differentially Associated with Aberrant Promotor Methylation in MDS Hematopoietic Progenitor Cells during Lineage Specific Differentiation." Blood 108, no. 11 (November 16, 2006): 2628. http://dx.doi.org/10.1182/blood.v108.11.2628.2628.

Full text

Abstract:

Abstract Recent findings suggest that in myelodysplastic syndrome (MDS) several key regulatory genes are affected by aberrant promotor methylation. To explore the molecular basis of this impairment we have generated an in vitro model of MDS lineage-specific hematopoietic differentiation by culturing CD34+ cells from healthy donors (n=7) and MDS patients (low risk: RA/n=6, RARS/n=3; high risk: RAEB/n=4, RAEB-T/n=2) with EPO, TPO and GCSF. Cell harvest was at days 0, 4, 7 and 11. Promotor methylation analysis of key genes involved in the control of apoptosis (p73, survivin, DAPK), DNA-repair (hMLH1), differentiation (RARb, WT1) and cell cycle control (p14, p15, p16, CHK2) was performed by methylation specific PCR of bisulfite treated genomic DNA for each lineage at each time point. In addition, expression of DNMT1 (maintenance DNA methyltransferase), DNMT3a and DNMT3b (both de novo DNA methyltransferase) was analyzed by real time RT-PCR and correlated with gene promotor methylation at any time point. DNMT1 expression was increased during erythropoiesis in both, normal controls and MDS patients. On the other hand, expression of de novo DNMTs was elevated during thrombopoiesis at all time points. During erythropoiesis hypermethylation of p73, hMLH1 and RARb was associated with elevated DNMT1, hypermethylation of p15, p16, p73 and survivin was positively associated with increasing DNMT3 expression. Interestingly, DNMT1 was only elevated in low risk MDS, but not further increased in high risk MDS patients. Surprisingly, MDS specific survivin promotor methylation was inverse correlated with DNTM1 and DNMT3a expression. However, a negative correlation of DNMT3a with survivin expression was found in low risk MDS but not in high risk MDS. In summary our data indicate that all mammalian DNMT isoforms may be involved in the aberrant DNA-methylation phenotype in MDS. Elevated DNMT1 expression may in particular contribute to ineffective erythropoiesis in low risk MDS. DNMT3a and 3b were elevated during megakaryopoiesis and their expression was inversely correlated with MDS disease risk (IPSS). We conclude that the knowledge about distinct expression patterns of DNMT isoforms in hematopoiesis may be of help for further strategies to implicate DNMT-inhibitors in the treatment of patients with MDS.

APA, Harvard, Vancouver, ISO, and other styles

22

Raddatz, G., P. M. Guzzardo, N. Olova, M. R. Fantappie, M. Rampp, M. Schaefer, W. Reik, G. J. Hannon, and F. Lyko. "Dnmt2-dependent methylomes lack defined DNA methylation patterns." Proceedings of the National Academy of Sciences 110, no. 21 (May 2, 2013): 8627–31. http://dx.doi.org/10.1073/pnas.1306723110.

Full text

APA, Harvard, Vancouver, ISO, and other styles

23

Khan, Shagufta, Divya Tej Sowpati, Arumugam Srinivasan, Mamilla Soujanya, and Rakesh K. Mishra. "Long-Read Genome Sequencing and Assembly of Leptopilina boulardi: A Specialist Drosophila Parasitoid." G3: Genes|Genomes|Genetics 10, no. 5 (March 26, 2020): 1485–94. http://dx.doi.org/10.1534/g3.120.401151.

Full text

Abstract:

Leptopilinaboulardi (Hymenoptera: Figitidae) is a specialist parasitoid of Drosophila. The Drosophila-Leptopilina system has emerged as a suitable model for understanding several aspects of host-parasitoid biology. However, a good quality genome of the wasp counterpart was lacking. Here, we report a whole-genome assembly of L. boulardi to bring it in the scope of the applied and fundamental research on Drosophila parasitoids with access to epigenomics and genome editing tools. The 375Mb draft genome has an N50 of 275Kb with 6315 scaffolds >500bp and encompasses >95% complete BUSCOs. Using a combination of ab-initio and RNA-Seq based methods, 25259 protein-coding genes were predicted and 90% (22729) of them could be annotated with at least one function. We demonstrate the quality of the assembled genome by recapitulating the phylogenetic relationship of L. boulardi with other Hymenopterans. The key developmental regulators like Hox genes and sex determination genes are well conserved in L. boulardi, and so is the basic toolkit for epigenetic regulation. The search for epigenetic regulators has also revealed that L. boulardi genome possesses DNMT1 (maintenance DNA methyltransferase), DNMT2 (tRNA methyltransferase) but lacks the de novo DNA methyltransferase (DNMT3). Also, the heterochromatin protein 1 family appears to have expanded as compared to other hymenopterans. The draft genome of L. boulardi (Lb17) will expedite the research on Drosophila parasitoids. This genome resource and early indication of epigenetic aspects in its specialization make it an interesting system to address a variety of questions on host-parasitoid biology.

APA, Harvard, Vancouver, ISO, and other styles

24

Katoh, Mariko, Tomaz Curk, Qikai Xu, Blaz Zupan, Adam Kuspa, and Gad Shaulsky. "Developmentally Regulated DNA Methylation in Dictyostelium discoideum." Eukaryotic Cell 5, no. 1 (January 2006): 18–25. http://dx.doi.org/10.1128/ec.5.1.18-25.2006.

Full text

Abstract:

ABSTRACT Methylation of cytosine residues in DNA plays a critical role in the silencing of gene expression, organization of chromatin structure, and cellular differentiation of eukaryotes. Previous studies failed to detect 5-methylcytosine in Dictyostelium genomic DNA, but the recent sequencing of the Dictyostelium genome revealed a candidate DNA methyltransferase gene (dnmA). The genome sequence also uncovered an unusual distribution of potential methylation sites, CpG islands, throughout the genome. DnmA belongs to the Dnmt2 subfamily and contains all the catalytic motifs necessary for cytosine methyltransferases. Dnmt2 activity is typically weak in Drosophila melanogaster, mouse, and human cells and the gene function in these systems is unknown. We have investigated the methylation status of Dictyostelium genomic DNA with antibodies raised against 5-methylcytosine and detected low levels of the modified nucleotide. We also found that DNA methylation increased during development. We searched the genome for potential methylation sites and found them in retrotransposable elements and in several other genes. Using Southern blot analysis with methylation-sensitive and -insensitive restriction endonucleases, we found that the DIRS retrotransposon and the guaB gene were indeed methylated. We then mutated the dnmA gene and found that DNA methylation was reduced to about 50% of the wild-type level. The mutant cells exhibited morphological defects in late development, indicating that DNA methylation has a regulatory role in Dictyostelium development. Our findings establish a role for a Dnmt2 methyltransferase in eukaryotic development.

APA, Harvard, Vancouver, ISO, and other styles

25

Zhou, Zehao, Huan-Qiu Li, and Feng Liu. "DNA Methyltransferase Inhibitors and their Therapeutic Potential." Current Topics in Medicinal Chemistry 18, no. 28 (February 12, 2019): 2448–57. http://dx.doi.org/10.2174/1568026619666181120150122.

Full text

Abstract:

Aberrant DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is associated with not only various cancers by silencing of tumor suppressor genes but also other diseases. The DNMTs, especially the DNMT1, DNMT3A and DNMT3B, are often overexpressed in various cancer tissues and cell lines. DNMTs are important epigenetic targets for drug development since the DNA methylation is reversible. This review summarizes an array of nucleoside and non-nucleoside inhibitors of DNMTs, as well as their biological activities. Among these inhibitors, the nucleoside analogue azacytidine and its deoxy derivative decitabine are both irreversible DNMT inhibitors and approved for the treatment of myelodysplastic syndrome.

APA, Harvard, Vancouver, ISO, and other styles

26

Zhang, Jiayu, Cheng Yang, Chunfu Wu, Wei Cui, and Lihui Wang. "DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy." Cancers 12, no. 8 (July 31, 2020): 2123. http://dx.doi.org/10.3390/cancers12082123.

Full text

Abstract:

DNA methyltransferases are an essential class of modifiers in epigenetics. In mammals, DNMT1, DNMT3A and DNMT3B participate in DNA methylation to regulate normal biological functions, such as embryo development, cell differentiation and gene transcription. Aberrant functions of DNMTs are frequently associated with tumorigenesis. DNMT aberrations usually affect tumor-related factors, such as hypermethylated suppressor genes and genomic instability, which increase the malignancy of tumors, worsen the prognosis for patients, and greatly increase the difficulty of cancer therapy. However, the impact of DNMTs on tumors is still controversial, and therapeutic approaches targeting DNMTs are still under exploration. Here, we summarize the biological functions and paradoxes associated with DNMTs and we discuss some emerging strategies for targeting DNMTs in tumors, which may provide novel ideas for cancer therapy.

APA, Harvard, Vancouver, ISO, and other styles

27

Ito, Takamasa, Musashi Kubiura-Ichimaru, Yuri Murakami, Aaron B. Bogutz, Louis Lefebvre, Isao Suetake, Shoji Tajima, and Masako Tada. "DNMT1 regulates the timing of DNA methylation by DNMT3 in an enzymatic activity-dependent manner in mouse embryonic stem cells." PLOS ONE 17, no. 1 (January 5, 2022): e0262277. http://dx.doi.org/10.1371/journal.pone.0262277.

Full text

Abstract:

DNA methylation (DNAme; 5-methylcytosine, 5mC) plays an essential role in mammalian development, and the 5mC profile is regulated by a balance of opposing enzymatic activities: DNA methyltransferases (DNMTs) and Ten-eleven translocation dioxygenases (TETs). In mouse embryonic stem cells (ESCs), de novo DNAme by DNMT3 family enzymes, demethylation by the TET-mediated conversion of 5mC to 5-hydroxymethylation (5hmC), and maintenance of the remaining DNAme by DNMT1 are actively repeated throughout cell cycles, dynamically forming a constant 5mC profile. Nevertheless, the detailed mechanism and physiological significance of this active cyclic DNA modification in mouse ESCs remain unclear. Here by visualizing the localization of DNA modifications on metaphase chromosomes and comparing whole-genome methylation profiles before and after the mid-S phase in ESCs lacking Dnmt1 (1KO ESCs), we demonstrated that in 1KO ESCs, DNMT3-mediated remethylation was interrupted during and after DNA replication. This results in a marked asymmetry in the distribution of 5hmC between sister chromatids at mitosis, with one chromatid being almost no 5hmC. When introduced in 1KO ESCs, the catalytically inactive form of DNMT1 (DNMT1CI) induced an increase in DNAme in pericentric heterochromatin and the DNAme-independent repression of IAPEz, a retrotransposon family, in 1KO ESCs. However, DNMT1CI could not restore the ability of DNMT3 to methylate unmodified dsDNA de novo in S phase in 1KO ESCs. Furthermore, during in vitro differentiation into epiblasts, 1KO ESCs expressing DNMT1CI showed an even stronger tendency to differentiate into the primitive endoderm than 1KO ESCs and were readily reprogrammed into the primitive streak via an epiblast-like cell state, reconfirming the importance of DNMT1 enzymatic activity at the onset of epiblast differentiation. These results indicate a novel function of DNMT1, in which DNMT1 actively regulates the timing and genomic targets of de novo methylation by DNMT3 in an enzymatic activity-dependent and independent manner, respectively.

APA, Harvard, Vancouver, ISO, and other styles

28

Kunert, N. "A Dnmt2-like protein mediates DNA methylation in Drosophila." Development 130, no. 21 (August 27, 2003): 5083–90. http://dx.doi.org/10.1242/dev.00716.

Full text

APA, Harvard, Vancouver, ISO, and other styles

29

Kiani, Jafar, Valérie Grandjean, Reinhard Liebers, Francesca Tuorto, Hossein Ghanbarian, Frank Lyko, François Cuzin, and Minoo Rassoulzadegan. "RNA–Mediated Epigenetic Heredity Requires the Cytosine Methyltransferase Dnmt2." PLoS Genetics 9, no. 5 (May 23, 2013): e1003498. http://dx.doi.org/10.1371/journal.pgen.1003498.

Full text

APA, Harvard, Vancouver, ISO, and other styles

30

Li, Sisi, Jiamu Du, Hui Yang, Juan Yin, Jianping Ding, and Jiang Zhong. "Functional and structural characterization of DNMT2 from Spodoptera frugiperda." Journal of Molecular Cell Biology 5, no. 1 (October 25, 2012): 64–66. http://dx.doi.org/10.1093/jmcb/mjs057.

Full text

APA, Harvard, Vancouver, ISO, and other styles

31

Mohan, K. Naga. "Stem Cell Models to Investigate the Role of DNA Methylation Machinery in Development of Neuropsychiatric Disorders." Stem Cells International 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/4379425.

Full text

Abstract:

Epigenetic mechanisms underlie differentiation of pluripotent stem cells into different lineages that contain identical genomes but express different sets of cell type-specific genes. Because of high discordance rates in monozygotic twins, epigenetic mechanisms are also implicated in development of neuropsychiatric disorders such as schizophrenia and autism. In support of this notion, increased levels of DNA methyltransferases (DNMTs), DNMT polymorphisms, and dysregulation of DNA methylation network were reported among schizophrenia patients. These results point to the importance of development of DNA methylation machinery-based models for studying the mechanism of abnormal neurogenesis due to certain DNMT alleles or dysregulated DNMTs. Achieving this goal is strongly confronted by embryonic lethality associated with altered levels of epigenetic machinery such as DNMT1 and expensive approaches in developingin vivomodels. In light of literature evidence that embryonic stem cells (ESCs) are tolerant of DNMT mutations and advancement in the technology of gene targeting, it is now possible to introduce desired mutations in DNMT loci to generate suitable ESC lines that can help understand the underlying mechanisms by which abnormal levels of DNMTs or their specific mutations/alleles result in abnormal neurogenesis. In the future, these models can facilitate development of suitable drugs for treatment of neuropsychiatric disorders.

APA, Harvard, Vancouver, ISO, and other styles

32

Park, Joo-Hoo, Jae-Min Shin, Hyun-Woo Yang, and Il-Ho Park. "DNMTs Are Involved in TGF-β1-Induced Epithelial–Mesenchymal Transitions in Airway Epithelial Cells." International Journal of Molecular Sciences 23, no. 6 (March 10, 2022): 3003. http://dx.doi.org/10.3390/ijms23063003.

Full text

Abstract:

Chronic rhinosinusitis (CRS) pathogenesis is closely related to tissue remodeling, including epithelial–mesenchymal transition (EMT). Epigenetic mechanisms play key roles in EMT. DNA methylation, mediated by DNA methyltransferases (DNMTs), is an epigenetic marker that is critical to EMT. The goal of this study was to determine whether DNMTs were involved in TGF-β1-induced EMT and elucidate the underlying mechanisms in nasal epithelial cells and air–liquid interface cultures. Global DNA methylation and DNMT activity were quantified. DNMT expression was measured using real-time PCR (qRT–PCR) in human CRS tissues. mRNA and protein levels of DNMTs, E-cadherin, vimentin, α-SMA, and fibronectin were determined using RT–PCR and Western blotting, respectively. DNMT1, DNMT3A, and DNMT3B gene expression were knocked down using siRNA transfection. MAPK phosphorylation and EMT-related transcription factor levels were determined using Western blotting. Signaling pathways were analyzed using specific inhibitors of MAPK. We demonstrated these data in primary nasal epithelial cells and air–liquid interface cultures. Global DNA methylation, DNMT activity, and DNMT expression increased in CRS tissues. DNMT expression was positively correlated with Lund–McKay CT scores. TGF-β1 dose-dependently induced DNMT expression. Further, 5-Aza inhibited TGF-β1-induced DNMT, Snail, and Slug expression related to EMT, as well as p38 and JNK phosphorylation in A549 cells and TGF-β1-induced DNMT expression and EMT in primary nasal epithelial cells and air–liquid interface cultures. TGF-β1-induced DNMT expression leads to DNA methylation and EMT via p38, JNK, Snail, and Slug signaling pathways. Inhibition of DNMT suppressed the EMT process and therefore is potentially a CRS therapeutic strategy.

APA, Harvard, Vancouver, ISO, and other styles

33

Mohammadzadeh, Nooshin, Fatemeh Mosaffa, Ehsan Khadivi, Rosa Jahangiri, and Khadijeh Jamialahmadi. "Increased Expression of DNA Methyltransferase 1 and 3B Correlates with Tumor Grade in Laryngeal Squamous Cell Carcinoma." Pharmaceutical Sciences 27, no. 3 (October 29, 2020): 393–98. http://dx.doi.org/10.34172/ps.2020.86.

Full text

Abstract:

Background: DNA methyltransferase (DNMT) enzymes, encoded by DNMT1, DNMT3A andDNMT3B genes, play a major role in the development of cancers through aberrant promotermethylation. Due to little information about the biological and clinical significance of expressionchanges of these genes in Laryngeal Squamous Cell carcinoma (LSCC), the current study wasdesigned to evaluate the contribution of DNMTs expression as potential diagnostic biomarkersin progression of LSCC. Methods: DNMT1, DNMT3A and DNMT3B expressions in tumoral and normal tissues fromthirty-three LSCC patients were evaluated by relative comparative real-time PCR, prior toany therapeutic intervention. Relationship between genes expression and clinicopathologicalfeatures were also analyzed. Results: The mRNA expression levels of all three DNMTs (DNMT1, DNMT3A and DNMT3B)were significantly elevated in LSCC tumor specimens compared to that of non-tumor tissues(P<0.0001, P=0.011 and P<0.0001, respectively). The expression of DNMT1 and DNMT3Bwas strongly associated with histopathological tumor grade. Moreover, the mRNA expressionlevels of DNMT3A were significantly correlated with laryngopharyngeal reflux. No significantrelationships existed with other clinicopathological parameters. Conclusion: Data showed that the expression levels of DNMT1, DNMT3A and DNMT3Bmarkedly increased in LSCC tissues. DNMT1 and DNMT3B were mainly overexpressed in highgrade LSCC tumors, therefore, they may have a role in LSCC progression. It seems that thesegenes may serve as diagnostic biomarkers in development of LSCC.

APA, Harvard, Vancouver, ISO, and other styles

34

Maugeri, Andrea, Martina Barchitta, Maria Mazzone, Francesco Giuliano, Guido Basile, and Antonella Agodi. "Resveratrol Modulates SIRT1 and DNMT Functions and Restores LINE-1 Methylation Levels in ARPE-19 Cells under Oxidative Stress and Inflammation." International Journal of Molecular Sciences 19, no. 7 (July 20, 2018): 2118. http://dx.doi.org/10.3390/ijms19072118.

Full text

Abstract:

The role of epigenetic alterations in the pathogenesis of retinal degenerative diseases, including age-related macular degeneration (AMD), has been pending so far. Our study investigated the effect of oxidative stress and inflammation on DNA methyltransferases (DNMTs) and Sirtuin 1 (SIRT1) functions, as well as on long interspersed nuclear element-1 (LINE-1) methylation, in human retinal pigment epithelial (ARPE-19) cells. Therefore, we evaluated whether treatment with resveratrol may modulate DNMT and SIRT1 functions and restore changes in LINE-1 methylation. Cells were treated with 25 mU/mL glucose oxidase (GOx) or 10 µg/mL lipopolysaccharide (LPS) to mimic oxidative or inflammatory conditions, respectively. Oxidative stress decreased DNMT1, DNMT3a, DNMT3b, and SIRT1 expression (p-values < 0.05), as well as total DNMTs (−28.5%; p < 0.0001) and SIRT1 (−29.0%; p < 0.0001) activities. Similarly, inflammatory condition decreased DNMT1 and SIRT1 expression (p-values < 0.05), as well as total DNMTs (−14.9%; p = 0.007) and SIRT1 (−20.1%; p < 0.002) activities. Interestingly, GOx- and LPS-treated cells exhibited lower LINE-1 methylation compared to controls (p-values < 0.001). We also demonstrated that treatment with 10 μM resveratrol for 24 h counteracted the detrimental effect on DNMT and SIRT1 functions, and LINE-1 methylation, in cells under oxidative and inflammatory conditions. However, further studies should explore the perspectives of resveratrol as a suitable strategy for the prevention and/or treatment of retinal degenerative diseases.

APA, Harvard, Vancouver, ISO, and other styles

35

Heil, Caiti S. Smukowski. "No Detectable Effect of the DNA Methyltransferase DNMT2 onDrosophilaMeiotic Recombination." G3: Genes|Genomes|Genetics 4, no. 11 (August 27, 2014): 2095–100. http://dx.doi.org/10.1534/g3.114.012393.

Full text

APA, Harvard, Vancouver, ISO, and other styles

36

Jeltsch, Albert, Ann Ehrenhofer-Murray, Tomasz P. Jurkowski, Frank Lyko, Gunter Reuter, Serge Ankri, Wolfgang Nellen, Matthias Schaefer, and Mark Helm. "Mechanism and biological role of Dnmt2 in Nucleic Acid Methylation." RNA Biology 14, no. 9 (July 1, 2016): 1108–23. http://dx.doi.org/10.1080/15476286.2016.1191737.

Full text

APA, Harvard, Vancouver, ISO, and other styles

37

Ehrenhofer-Murray, Ann. "Cross-Talk between Dnmt2-Dependent tRNA Methylation and Queuosine Modification." Biomolecules 7, no. 4 (February 10, 2017): 14. http://dx.doi.org/10.3390/biom7010014.

Full text

APA, Harvard, Vancouver, ISO, and other styles

38

Hermann, Andrea, Sigrid Schmitt, and Albert Jeltsch. "The Human Dnmt2 Has Residual DNA-(Cytosine-C5) Methyltransferase Activity." Journal of Biological Chemistry 278, no. 34 (June 6, 2003): 31717–21. http://dx.doi.org/10.1074/jbc.m305448200.

Full text

APA, Harvard, Vancouver, ISO, and other styles

39

Ашапкин, В. В., Л. И. Кутуева, and Б. Ф. Ванюшин. "Dnmt2 – самая эволюционно консервативная и загадочная цитозиновая ДНК-метилтрансфераза эукариот." Генетика 52, no. 3 (2016): 269–82. http://dx.doi.org/10.7868/s0016675816030024.

Full text

APA, Harvard, Vancouver, ISO, and other styles

40

Jurkowski, Tomasz P., and Albert Jeltsch. "On the Evolutionary Origin of Eukaryotic DNA Methyltransferases and Dnmt2." PLoS ONE 6, no. 11 (November 30, 2011): e28104. http://dx.doi.org/10.1371/journal.pone.0028104.

Full text

APA, Harvard, Vancouver, ISO, and other styles

41

Vieira, Gilberto Cavalheiro, Gustavo Fioravanti Vieira, Marialva Sinigaglia, and Vera Lúcia da Silva Valente. "Linking epigenetic function to electrostatics: The DNMT2 structural model example." PLOS ONE 12, no. 6 (June 2, 2017): e0178643. http://dx.doi.org/10.1371/journal.pone.0178643.

Full text

APA, Harvard, Vancouver, ISO, and other styles

42

Zwergel, Clemens, Rossella Fioravanti, Giulia Stazi, Federica Sarno, Cecilia Battistelli, Annalisa Romanelli, Angela Nebbioso, et al. "Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation." Cancers 12, no. 2 (February 14, 2020): 447. http://dx.doi.org/10.3390/cancers12020447.

Full text

Abstract:

DNA methyltransferases (DNMTs) play a relevant role in epigenetic control of cancer cell survival and proliferation. Since only two DNMT inhibitors (azacitidine and decitabine) have been approved to date for the treatment of hematological malignancies, the development of novel potent and specific inhibitors is urgent. Here we describe the design, synthesis, and biological evaluation of a new series of compounds acting at the same time as DNMTs (mainly DNMT3A) inhibitors and degraders. Tested against leukemic and solid cancer cell lines, 2a–c and 4a–c (the last only for leukemias) displayed up to submicromolar antiproliferative activities. In HCT116 cells, such compounds induced EGFP gene expression in a promoter demethylation assay, confirming their demethylating activity in cells. In the same cell line, 2b and 4c chosen as representative samples induced DNMT1 and -3A protein degradation, suggesting for these compounds a double mechanism of DNMT3A inhibition and DNMT protein degradation.

APA, Harvard, Vancouver, ISO, and other styles

43

Wanga, Xin-zhi, Jia-li Gu, Ming Gao, Yong Bian, Jiang-yu Liang, Hong-mei Wen, and Hao Wu. "Peperomin E Induces Promoter Hypomethylation of Metastatic-Suppressor Genes and Attenuates Metastasis in Poorly Differentiated Gastric Cancer." Cellular Physiology and Biochemistry 50, no. 6 (2018): 2341–64. http://dx.doi.org/10.1159/000495096.

Full text

Abstract:

Background/Aims: Peperomin E (PepE), a natural secolignan isolated from the whole plant of Peperomia dindygulensis, has been reported by ourselves and others to display potent anti-cancer effects in many types cancer cells, especially gastric cancer. However, the effects of PepE on the metastasis of poorly-differentiated gastric cancer cells and the underlying molecular mechanisms have not been well elucidated. Methods: We evaluated PepE effects on gastric cancer cell invasion and migration in vitro via wound healing and transwell assays and those on growth and metastasis in vivo using an orthotopic xenograft NOD-SCID mouse model. DNA methyltransferase (DNMT) activity was determined using a colorimetric DNMT activity/inhibition assay kit. PepE binding kinetics to DNMTs were determined using the bio-layer interferometry binding assay. Gene and protein levels of DNMTs, AMPKα-Sp1 signaling molecules, and metastatic-suppressor genes in PepE-treated gastric cancer cells were determined using quantitative reverse transcription-PCR arrays and western blotting. The effect of PepE on Sp1 binding to the DNMT promoter was determined by electrophoretic mobility-shift assay. Global DNA methylation levels were determined using liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The methylation status of silenced metastatic-suppressor genes (MSGs) in gastric cancer cells was investigated by methylation-specific PCR. Results: PepE can dose-dependently suppress invasion and migration of poorly-differentiated gastric cancer cells in vitro and in vivo with low toxicity against normal cells. Mechanistically, PepE not only covalently binds to the catalytic domain of DNMT1 and inhibits its activity (IC50 value 3.61 μM) but also down-regulates DNMT1, 3a, and 3b mRNA and protein expression in in gastric cancer cells, by disruption of the physical interaction of Sp1 with the DNMT1, 3a, and 3b promoter and mediation of the AMPKα-Sp1 signaling pathway. The dual inhibition activity of PepE toward DNMTs renders a relative global DNA hypomethylation, which induces MSG promoter hypomethylation (e.g., E-cadherin and TIMP3) and enhances their expression in gastric cancer cells. Conclusion: Collectively, our data indicated that PepE may represent a promising therapeutic lead compound for intervention in gastric cancer metastasis and may also exhibit potential as a DNA methylation inhibitor for use in epigenetic cancer therapy.

APA, Harvard, Vancouver, ISO, and other styles

44

Myant, Kevin, and Irina Stancheva. "LSH Cooperates with DNA Methyltransferases To Repress Transcription." Molecular and Cellular Biology 28, no. 1 (October 29, 2007): 215–26. http://dx.doi.org/10.1128/mcb.01073-07.

Full text

Abstract:

ABSTRACT LSH, a protein related to the SNF2 family of chromatin-remodeling ATPases, is required for efficient DNA methylation in mammals. How LSH functions to support DNA methylation and whether it associates with a large protein complex containing DNA methyltransferase (DNMT) enzymes is currently unclear. Here we show that, unlike many other chromatin-remodeling ATPases, native LSH is present mostly as a monomeric protein in nuclear extracts of mammalian cells and cannot be detected in a large multisubunit complex. However, when targeted to a promoter of a reporter gene, LSH acts as an efficient transcriptional repressor. Using this as an assay to identify proteins that are required for LSH-mediated repression we found that LSH cooperates with the DNMTs DNMT1 and DNMT3B and with the histone deacetylases (HDACs) HDAC1 and HDAC2 to silence transcription. We show that transcriptional repression by LSH and interactions with HDACs are lost in DNMT1 and DNMT3B knockout cells but that the enzymatic activities of DNMTs are not required for LSH-mediated silencing. Our data suggest that LSH serves as a recruiting factor for DNMTs and HDACs to establish transcriptionally repressive chromatin which is perhaps further stabilized by DNA methylation at targeted loci.

APA, Harvard, Vancouver, ISO, and other styles

45

Qureshi, Muhammad Zahid, Uteuliyev Yerzhan Sabitaliyevich, Marat Rabandiyarov, and Arystanbekov Talant Arystanbekuly. "Role of DNA Methyltransferases (DNMTs) in metastasis." Cellular and Molecular Biology 68, no. 1 (May 22, 2022): 226–36. http://dx.doi.org/10.14715/cmb/2022.68.1.27.

Full text

Abstract:

The DNA methyltransferase (DNMT) family constitutes a conserved set of DNA-modifying enzymes which have essential functions in the modulation of epigenetics. The fundamental role of epigenetic changes in carcinogenesis and metastasis is increasingly being appreciated. DNMTs (DNMT1, DNMT3A and DNMT3B) have been shown to drive metastasis. Epigenetic machinery is installed at the target sites for the regulation of a wide variety of genes. Moreover, microRNAs, long non-coding RNAs and circular RNAs also shape the epigenetic landscape during metastasis. In this review, we have provided a snapshot of the quintessential role of DNMTs in metastasis. We also summarize how lncRNAs and circRNAs play roles in the epigenetic regulation of a myriad of genes.

APA, Harvard, Vancouver, ISO, and other styles

46

Ross, Jason P., Isao Suetake, Shoji Tajima, and Peter L. Molloy. "Recombinant mammalian DNA methyltransferase activity on model transcriptional gene silencing short RNA–DNA heteroduplex substrates." Biochemical Journal 432, no. 2 (November 12, 2010): 323–32. http://dx.doi.org/10.1042/bj20100579.

Full text

Abstract:

The biochemical mechanism of short RNA-induced TGS (transcriptional gene silencing) in mammals is unknown. Two competing models exist; one suggesting that the short RNA interacts with a nascent transcribed RNA strand (RNA–RNA model) and the other implying that short RNA forms a heteroduplex with DNA from the unwound double helix, an R-loop structure (RNA–DNA model). Likewise, the requirement for DNA methylation to enact TGS is still controversial. In vitro assays using purified recombinant murine Dnmt (DNA methyltransferase) 1-dN (where dN indicates an N-terminal truncation), 3a and 3b enzymes and annealed oligonucleotides were designed to question whether Dnmts methylate DNA in a RNA–DNA heteroduplex context and whether a RNA–DNA heteroduplex R-loop is a good substrate for Dnmts. Specifically, model synthetic oligonucleotides were used to examine methylation of single-stranded oligonucleotides, annealed oligonucleotide duplexes, RNA–DNA heteroduplexes, DNA bubbles and R-loops. Dnmt methylation activity on the model substrates was quantified with initial velocity assays, novel ARORA (annealed RNA and DNA oligonucleotide-based methylation-sensitive restriction enzyme analysis), tBS (tagged-bisulfite sequencing) and the quantitative PCR-based method MethylQuant. We found that RNA–DNA heteroduplexes and R-loops are poor substrates for methylation by both the maintenance (Dnmt1) and de novo (Dnmt3a and Dnmt3b) Dnmts. These results suggest the proposed RNA/DNA model of TGS in mammals is unlikely. Analysis of tagged-bisulfite genomic sequencing led to the unexpected observation that Dnmt1-dN can methylate cytosines in a non-CpG context in DNA bubbles. This may have relevance in DNA replication and silencing of transcriptionally active loci in vivo.

APA, Harvard, Vancouver, ISO, and other styles

47

Thiagarajan, Devi, Rachana Roshan Dev, and Sanjeev Khosla. "The DNA methyltranferase Dnmt2 participates in RNA processing during cellular stress." Epigenetics 6, no. 1 (January 2011): 103–13. http://dx.doi.org/10.4161/epi.6.1.13418.

Full text

APA, Harvard, Vancouver, ISO, and other styles

48

Müller, Martin, Mark Hartmann, Isabelle Schuster, Sebastian Bender, Kathrin L. Thüring, Mark Helm, Jon R. Katze, Wolfgang Nellen, Frank Lyko, and Ann E. Ehrenhofer-Murray. "Dynamic modulation of Dnmt2-dependent tRNA methylation by the micronutrient queuine." Nucleic Acids Research 43, no. 22 (September 30, 2015): 10952–62. http://dx.doi.org/10.1093/nar/gkv980.

Full text

APA, Harvard, Vancouver, ISO, and other styles

49

Hertz, Rivi, Ayala Tovy, Michael Kirschenbaum, Meirav Geffen, Tomoyoshi Nozaki, Noam Adir, and Serge Ankri. "The Entamoeba histolytica Dnmt2 Homolog (Ehmeth) Confers Resistance to Nitrosative Stress." Eukaryotic Cell 13, no. 4 (February 21, 2014): 494–503. http://dx.doi.org/10.1128/ec.00031-14.

Full text

Abstract:

ABSTRACT Nitric oxide (NO) has antimicrobial properties against many pathogens due to its reactivity as an S-nitrosylating agent. It inhibits many of the key enzymes that are involved in the metabolism and virulence of the parasite Entamoeba histolytica through S-nitrosylation of essential cysteine residues. Very little information is available on the mechanism of resistance to NO by pathogens in general and by this parasite in particular. Here, we report that exposure of the parasites to S -nitrosoglutathione (GSNO), an NO donor molecule, strongly reduces their viability and protein synthesis. However, the deleterious effects of NO were significantly reduced in trophozoites overexpressing Ehmeth, the cytosine-5 methyltransferase of the Dnmt2 family. Since these trophozoites also exhibited high levels of tRNA Asp methylation, the high levels suggested that Ehmeth-mediated tRNA Asp methylation is part of the resistance mechanism to NO. We previously reported that enolase, another glycolytic enzyme, binds to Ehmeth and inhibits its activity. We observed that the amount of Ehmeth-enolase complex was significantly reduced in GSNO-treated E. histolytica , which explains the aforementioned increase of tRNA methylation. Specifically, we demonstrated via site-directed mutagenesis that cysteine residues 228 and 229 of Ehmeth are susceptible to S-nitrosylation and are crucial for Ehmeth binding to enolase and for Ehmeth-mediated resistance to NO. These results indicate that Ehmeth has a central role in the response of the parasite to NO, and they contribute to the growing evidence that NO is a regulator of epigenetic mechanisms.

APA, Harvard, Vancouver, ISO, and other styles

50

Jeltsch, Albert, Wolfgang Nellen, and Frank Lyko. "Two substrates are better than one: dual specificities for Dnmt2 methyltransferases." Trends in Biochemical Sciences 31, no. 6 (June 2006): 306–8. http://dx.doi.org/10.1016/j.tibs.2006.04.005.

Full text

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'DNMT2'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles