scholarly journals The DNA Methylation Landscape of Giant Viruses

2019 ◽  
Author(s):  
Sandra Jeudy ◽  
Sofia Rigou ◽  
Jean-Marie Alempic ◽  
Jean-Michel Claverie ◽  
Chantal Abergel ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Molecule ◽  
Defense Mechanism ◽  
Methylation Status ◽  
Purifying Selection ◽  
Dna Methyltransferases ◽  
Epigenetic Mark ◽  
Host Defense Mechanism ◽  
Domains Of Life ◽  
Giant Viruses

AbstractDNA methylation is an important epigenetic mark that contributes to various regulations in all domains of life. Prokaryotes use it through Restriction-Modification (R-M) systems as a host-defense mechanism against viruses. The recently discovered giant viruses are widespread dsDNA viruses infecting eukaryotes with gene contents overlapping the cellular world. While they are predicted to encode DNA methyltransferases (MTases), virtually nothing is known about the DNA methylation status of their genomes. Using single-molecule real-time sequencing we studied the complete methylome of a large spectrum of families: the Marseilleviridae, the Pandoraviruses, the Molliviruses, the Mimiviridae along with their associated virophages and transpoviron, the Pithoviruses and the Cedratviruses (of which we report a new strain). Here we show that DNA methylation is widespread in giant viruses although unevenly distributed. We then identified the corresponding viral MTases, all of which are of bacterial origins and subject to intricate gene transfers between bacteria, viruses and their eukaryotic host. If some viral MTases undergo pseudogenization, most are conserved, functional and under purifying selection, suggesting that they increase the viruses’ fitness. While the Marseilleviridae, Pithoviruses and Cedratviruses DNA MTases catalyze N6-methyl-adenine modifications, some MTases of Molliviruses and Pandoraviruses unexpectedly catalyze the formation of N4-methyl-cytosine modifications. In Marseilleviridae, encoded MTases are paired with cognate restriction endonucleases (REases) forming complete R-M systems. Our data suggest that giant viruses MTases could be involved in different kind of virus-virus interactions during coinfections.

scholarly journals Physical Activity and DNA Methylation in Humans

2021 ◽  
Vol 22 (23) ◽  
pp. 12989
Author(s):  
Witold Józef Światowy ◽  
Hanna Drzewiecka ◽  
Michalina Kliber ◽  
Maria Sąsiadek ◽  
Paweł Karpiński ◽  
...  
Keyword(s):  
Gene Expression ◽  
Physical Activity ◽  
Dna Methylation ◽  
Current Knowledge ◽  
Methylation Status ◽  
Cpg Islands ◽  
Great Majority ◽  
Dna Methyltransferases ◽  
Epigenetic Mark ◽  
Cpg Dinucleotides

Physical activity is a strong stimulus influencing the overall physiology of the human body. Exercises lead to biochemical changes in various tissues and exert an impact on gene expression. Exercise-induced changes in gene expression may be mediated by epigenetic modifications, which rearrange the chromatin structure and therefore modulate its accessibility for transcription factors. One of such epigenetic mark is DNA methylation that involves an attachment of a methyl group to the fifth carbon of cytosine residue present in CG dinucleotides (CpG). DNA methylation is catalyzed by a family of DNA methyltransferases. This reversible DNA modification results in the recruitment of proteins containing methyl binding domain and further transcriptional co-repressors leading to the silencing of gene expression. The accumulation of CpG dinucleotides, referred as CpG islands, occurs at the promoter regions in a great majority of human genes. Therefore, changes in DNA methylation profile affect the transcription of multiple genes. A growing body of evidence indicates that exercise training modulates DNA methylation in muscles and adipose tissue. Some of these epigenetic markers were associated with a reduced risk of chronic diseases. This review summarizes the current knowledge about the influence of physical activity on the DNA methylation status in humans.

scholarly journals Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

2018 ◽  
Vol 19 (10) ◽  
pp. 3106 ◽  
Author(s):  
Kuniyasu Soda
Keyword(s):  
Dna Methylation ◽  
Carbon Metabolism ◽  
Methylation Status ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Dna Methyltransferases ◽  
Polyamine Metabolism ◽  
Methyl Group ◽  
Wide Range ◽  
One Carbon Metabolism

Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.

scholarly journals Modeling DNA Methylation Profiles through a Dynamic Equilibrium between Methylation and Demethylation

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1271
Author(s):  
Giulia De Riso ◽  
Damiano Francesco Giuseppe Fiorillo ◽  
Annalisa Fierro ◽  
Mariella Cuomo ◽  
Lorenzo Chiariotti ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dynamic Equilibrium ◽  
Dynamic Balance ◽  
Methylation Status ◽  
Regulatory Mechanisms ◽  
Epigenetic Mark ◽  
Transcription Start ◽  
Depth Analysis ◽  
High Depth ◽  
Methylation Profiling

DNA methylation is a heritable epigenetic mark that plays a key role in regulating gene expression. Mathematical modeling has been extensively applied to unravel the regulatory mechanisms of this process. In this study, we aimed to investigate DNA methylation by performing a high-depth analysis of particular loci, and by subsequent modeling of the experimental results. In particular, we performed an in-deep DNA methylation profiling of two genomic loci surrounding the transcription start site of the D-Aspartate Oxidase and the D-Serine Oxidase genes in different samples (n = 51). We found evidence of cell-to-cell differences in DNA methylation status. However, these cell differences were maintained between different individuals, which indeed showed very similar DNA methylation profiles. Therefore, we hypothesized that the observed pattern of DNA methylation was the result of a dynamic balance between DNA methylation and demethylation, and that this balance was identical between individuals. We hence developed a simple mathematical model to test this hypothesis. Our model reliably captured the characteristics of the experimental data, suggesting that DNA methylation and demethylation work together in determining the methylation state of a locus. Furthermore, our model suggested that the methylation status of neighboring cytosines plays an important role in this balance.

PPARγ preservation via promoter demethylation alleviates osteoarthritis in mice

2019 ◽  
Vol 78 (10) ◽  
pp. 1420-1429 ◽  
Author(s):  
Xiaobo Zhu ◽  
Fang Chen ◽  
Ke Lu ◽  
Ai Wei ◽  
Qing Jiang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Knockout Mice ◽  
Cartilage Damage ◽  
Critical Role ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Dna Methyltransferases ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Peroxisome Proliferator

ObjectivesOsteoarthritis (OA) is the most common degenerative joint disease in aged population and its development is significantly influenced by aberrant epigenetic modifications of numerous OA susceptible genes; however, the precise mechanisms that DNA methylation alterations affect OA pathogenesis remain undefined. This study investigates the critical role of epigenetic PPARγ (peroxisome proliferator–activated receptor-gamma) suppression in OA development.MethodsArticular cartilage expressions of PPARγ and bioactive DNA methyltransferases (DNMTs) from OA patients and mice incurred by DMM (destabilisation of medial meniscus) were examined. DNA methylation status of both human and mouse PPARγ promoters were assessed by methylated specific PCR and/or bisulfite-sequencing PCR. OA protections by a pharmacological DNA demethylating agent 5Aza (5-Aza-2'-deoxycytidine) were compared between wild type and PPARγ knockout mice.ResultsArticular cartilages from both OA patients and DMM mice display substantial PPARγ suppressions likely due to aberrant elevations of DNMT1 and DNMT3a and consequential PPARγ promoter hypermethylation. 5Aza known to inhibit both DNMT1 and DNMT3a reversed the PPARγ promoter hypermethylation, recovered the PPARγ loss and effectively attenuated the cartilage damage in OA mice. 5Aza also inhibited the OA-associated excessive inflammatory cytokines and deficit anti-oxidant enzymes, which were blocked by a specific PPARγ inhibitor in cultured chondrocytes. Further, 5Aza-confered protections against the cartilage damage and the associated abnormalities of OA-susceptible factors were significantly abrogated in PPARγ knockout mice.ConclusionEpigenetic PPARγ suppression plays a key role in OA development and PPARγ preservation via promoter demethylation possesses promising therapeutic potentials in clinical treatment of OA and the related joint diseases.

scholarly journals Diverse DNA modification in marine prokaryotic and viral communities

2021 ◽  
Author(s):  
Satoshi Hiraoka ◽  
Tomomi Sumida ◽  
Miho Hirai ◽  
Atsushi Toyoda ◽  
Shinsuke Kawagucci ◽  
...  
Keyword(s):  
Microbial Communities ◽  
Single Molecule ◽  
Evolutionary History ◽  
Defense Mechanism ◽  
Dna Methyltransferases ◽  
Dna Modifications ◽  
History Of ◽  
Viral Communities ◽  
Metagenomic Assembly ◽  
Marine Microbial Communities

Chemical modifications of DNA, including methylation, play an important role in prokaryotes and viruses. However, our knowledge of the modification systems in environmental microbial communities, typically dominated by members not yet cultured, is limited. Here, we conducted 'metaepigenomic' analyses by single-molecule real-time sequencing of marine microbial communities. In total, 233 and 163 metagenomic assembly genomes (MAGs) were constructed from diverse prokaryotes and viruses, respectively, and 220 modified motifs and 276 DNA methyltransferases (MTases) were identified. Most of the MTases were not associated with the defense mechanism. The MTase-motif correspondence found in the MAGs revealed 10 novel pairs, and experimentally confirmed the catalytic specificities of the MTases. We revealed novel alternative motifs in the methylation system that are highly conserved in Alphaproteobacteria, illuminating the co-evolutionary history of the methylation system and host genome. Our findings highlight diverse unexplored DNA modifications that potentially affect the ecology and evolution of prokaryotes and viruses.

scholarly journals Editing DNA Methylation in Mammalian Embryos

2020 ◽  
Vol 21 (2) ◽  
pp. 637 ◽  
Author(s):  
Taiga Yamazaki ◽  
Yu Hatano ◽  
Ryoya Taniguchi ◽  
Noritada Kobayashi ◽  
Kazuo Yamagata
Keyword(s):  
Dna Methylation ◽  
Transcriptional Regulation ◽  
Gene Knockout ◽  
Methylation Status ◽  
Dna Methyltransferases ◽  
Biological Functions ◽  
Epigenome Editing ◽  
Early Embryos ◽  
Mammalian Embryos ◽  
Genomic Regions

DNA methylation in mammals is essential for numerous biological functions, such as ensuring chromosomal stability, genomic imprinting, and X-chromosome inactivation through transcriptional regulation. Gene knockout of DNA methyltransferases and demethylation enzymes has made significant contributions to analyzing the functions of DNA methylation in development. By applying epigenome editing, it is now possible to manipulate DNA methylation in specific genomic regions and to understand the functions of these modifications. In this review, we first describe recent DNA methylation editing technology. We then focused on changes in DNA methylation status during mammalian gametogenesis and preimplantation development, and have discussed the implications of applying this technology to early embryos.

scholarly journals Epigenetic alteration of the donor cells does not recapitulate the reprogramming of DNA methylation in cloned embryos

Reproduction ◽  
2007 ◽  
Vol 134 (6) ◽  
pp. 781-787 ◽  
Author(s):  
Gabbine Wee ◽  
Jung-Jae Shim ◽  
Deog-Bon Koo ◽  
Jung-Il Chae ◽  
Kyung-Kwang Lee ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Trichostatin A ◽  
Dna Methyltransferases ◽  
Epigenetic Reprogramming ◽  
Preimplantation Development ◽  
Developmental Competence ◽  
Epigenetic Mark ◽  
Satellite Sequence ◽  
Donor Cells

Epigenetic reprogramming is a prerequisite process during mammalian development that is aberrant in cloned embryos. However, mechanisms that evolve abnormal epigenetic reprogramming during preimplantation development are unclear. To trace the molecular event of an epigenetic mark such as DNA methylation, bovine fibroblasts were epigeneticallyaltered by treatment with trichostatin A (TSA) and then individually transferred into enucleated bovine oocytes. In the TSA-treated cells, expression levels of histone deacetylases and DNA methyltransferases were reduced, but the expression level of histone acetyltransferases such as Tip60 and histone acetyltransferase 1 (HAT1) did not change compared with normal cells. DNA methylation levels of non-treated (normal) and TSA-treated cells were 64.0 and 48.9% in the satellite I sequence (P < 0.05) respectively, and 71.6 and 61.9% in the α-satellite sequence respectively. DNA methylation levels of nuclear transfer (NT) and TSA-NT blastocysts in the satellite I sequence were 67.2 and 42.2% (P < 0.05) respectively, which was approximately similar to those of normal and TSA-treated cells. In the α-satellite sequence, NT and TSA-NT embryos were substantially demethylated at the blastocyst stage as IVF-derived embryos were demethylated. The in vitro developmental rate (46.6%) of TSA-NT embryos that were individually transferred with TSA-treated cells was higher than that (31.7%) of NT embryos with non-treated cells (P < 0.05). Our findings suggest that the chromatin of a donor cell is unyielding to the reprogramming of DNA methylation during preimplantation development, and that alteration of the epigenetic state of donor cells may improve in vitro developmental competence of cloned embryos.

scholarly journals Metaepigenomic analysis reveals the unexplored diversity of DNA methylation in an environmental prokaryotic community

2018 ◽  
Author(s):  
Satoshi Hiraoka ◽  
Yusuke Okazaki ◽  
Mizue Anda ◽  
Atsushi Toyoda ◽  
Shin-ichi Nakano ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Molecule ◽  
Defense Mechanisms ◽  
Lake Biwa ◽  
Dna Methyltransferases ◽  
Phage Infection ◽  
Prokaryotic Community ◽  
Powerful Approach ◽  
Diverse Groups ◽  
Circular Consensus Sequencing

AbstractDNA methylation plays important roles in prokaryotes, such as in defense mechanisms against phage infection, and the corresponding genomic landscapes—prokaryotic epigenomes—have recently begun to be disclosed. However, our knowledge of prokaryote methylation systems has been severely limited to those of culturable prokaryotes, whereas environmental communities are in fact dominated by uncultured members that must harbor much more diverse DNA methyltransferases. Here, using single-molecule real-time and circular consensus sequencing techniques, we revealed the ‘metaepigenomes’ of an environmental prokaryotic community in the largest lake in Japan, Lake Biwa. A total of 19 draft genomes from phylogenetically diverse groups, most of which are yet to be cultured, were successfully reconstructed. The analysis of DNA chemical modifications identified 29 methylated motifs in those genomes, among which 14 motifs were novel.Furthermore, we searched for the methyltransferase genes responsible for the methylation of the detected novel motifs and confirmed their catalytic specificities via transformation experiments involving artificially synthesized genes. Finally, we found that genomes without DNA methylation tended to exhibit higher phage infection levels than those with methylation. In summary, this study proves that metaepigenomics is a powerful approach for revealing the vast unexplored variety of prokaryotic DNA methylation systems in nature.

scholarly journals Long exposure to mature ooplasm can alter DNA methylation at imprinted loci in non-growing oocytes but not in prospermatogonia

Reproduction ◽  
2014 ◽  
Vol 147 (1) ◽  
pp. H1-H6 ◽  
Author(s):  
Yayoi Obata ◽  
Takuya Wakai ◽  
Satoshi Hara ◽  
Tomohiro Kono
Keyword(s):  
Dna Methylation ◽  
Methylation Status ◽  
Dna Methyltransferases ◽  
Chromatin Conformation ◽  
Differentially Methylated Regions ◽  
Newborn Mice ◽  
Male And Female ◽  
Conformation Changes ◽  
Old Mice

DNA methylation imprints that are established in spermatogenesis and oogenesis are essential for functional gametes. However, the mechanisms underlying gamete-specific imprinting remain unclear. In this study, we investigated whether male and female gametes derived from newborn mice are epigenetically plastic and whether DNA methylation imprints are influenced by the niche surrounding the nuclei of the gametes. When prospermatogonia possessing sperm-specific DNA methylation imprints were fused with enucleated fully grown oocytes and exposed to the ooplasm for 5–6 days, the DNA methylation status of the reconstituted oocytes remained identical to that of prospermatogonia for all the imprinted regions analysed. These results suggest that the imprinting status of prospermatogonia is stable and that the epigenome of prospermatogonia loses sexual plasticity. By contrast, when non-growing oocytes lacking oocyte-specific DNA methylation imprints were fused with enucleated fully grown oocytes and the reconstituted oocytes were then cultured for 5–6 days, theIgf2r,Kcnq1ot1and, unexpectedly,H19/Igf2differentially methylated regions (DMRs) were methylated. Methylation imprints were entirely absent in oocytes derived from 5-day-old mice, andH19/Igf2DMR is usually methylated only in spermatogenesis. These findings indicate that in the nuclei of non-growing oocytes the chromatin conformation changes and becomes permissive to DNA methyltransferases in some DMRs and that mechanisms for maintaining non-methylated status at theH19/Igf2DMR are lost upon long exposure to mature ooplasm.

scholarly journals Immunological Effects of Epigenetic Modifiers

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1911 ◽  
Author(s):  
Lucillia Bezu ◽  
Alejandra Wu Chuang ◽  
Peng Liu ◽  
Guido Kroemer ◽  
Oliver Kepp
Keyword(s):  
Dna Methylation ◽  
Histone Deacetylases ◽  
Methylation Status ◽  
Dna Methyltransferases ◽  
Cancer Hallmarks ◽  
Epigenetic Modifiers ◽  
Oncogenic Pathways ◽  
Immunotherapeutic Strategy ◽  
Immunological Effects ◽  
Molecular Patterns

Epigenetic alterations are associated with major pathologies including cancer. Epigenetic dysregulation, such as aberrant histone acetylation, altered DNA methylation, or modified chromatin organization, contribute to oncogenesis by inactivating tumor suppressor genes and activating oncogenic pathways. Targeting epigenetic cancer hallmarks can be harnessed as an immunotherapeutic strategy, exemplified by the use of pharmacological inhibitors of DNA methyltransferases (DNMT) and histone deacetylases (HDAC) that can result in the release from the tumor of danger-associated molecular patterns (DAMPs) on one hand and can (re-)activate the expression of tumor-associated antigens on the other hand. This finding suggests that epigenetic modifiers and more specifically the DNA methylation status may change the interaction of chromatin with chaperon proteins including HMGB1, thereby contributing to the antitumor immune response. In this review, we detail how epigenetic modifiers can be used for stimulating therapeutically relevant anticancer immunity when used as stand-alone treatments or in combination with established immunotherapies.

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