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

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.

2018 ◽  
Vol 19 (10) ◽  
pp. 3106 ◽  
Author(s):  
Kuniyasu Soda

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.


Epigenomics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 747-755
Author(s):  
Veronika Suni ◽  
Fatemeh Seyednasrollah ◽  
Bishwa Ghimire ◽  
Sini Junttila ◽  
Asta Laiho ◽  
...  

Aim: DNA methylation is a key epigenetic mechanism regulating gene expression. Identifying differentially methylated regions is integral to DNA methylation analysis and there is a need for robust tools reliably detecting regions with significant differences in their methylation status. Materials & methods: We present here a reproducibility-optimized test statistic (ROTS) for detection of differential DNA methylation from high-throughput sequencing or array-based data. Results: Using both simulated and real data, we demonstrate the ability of ROTS to identify differential methylation between sample groups. Conclusion: Compared with state-of-the-art methods, ROTS shows competitive sensitivity and specificity in detecting consistently differentially methylated regions.


2019 ◽  
Vol 78 (10) ◽  
pp. 1420-1429 ◽  
Author(s):  
Xiaobo Zhu ◽  
Fang Chen ◽  
Ke Lu ◽  
Ai Wei ◽  
Qing Jiang ◽  
...  

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.


2019 ◽  
Author(s):  
Sandra Jeudy ◽  
Sofia Rigou ◽  
Jean-Marie Alempic ◽  
Jean-Michel Claverie ◽  
Chantal Abergel ◽  
...  

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.


2020 ◽  
Vol 21 (2) ◽  
pp. 637 ◽  
Author(s):  
Taiga Yamazaki ◽  
Yu Hatano ◽  
Ryoya Taniguchi ◽  
Noritada Kobayashi ◽  
Kazuo Yamagata

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.


2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Yuanyuan Zhang ◽  
Shudong Wang ◽  
Xinzeng Wang

Background. DNA methylation is essential for regulating gene expression, and the changes of DNA methylation status are commonly discovered in disease. Therefore, identification of differentially methylation patterns, especially differentially methylated regions (DMRs), in two different groups is important for understanding the mechanism of complex diseases. Few tools exist for DMR identification through considering features of methylation data, but there is no comprehensive integration of the characteristics of DNA methylation data in current methods. Results. Accounting for the characteristics of methylation data, such as the correlation characteristics of neighboring CpG sites and the high heterogeneity of DNA methylation data, we propose a data-driven approach for DMR identification through evaluating the energy of single site using modified 1D Ising model. Applied to both simulated and publicly available datasets, our approach is compared with other popular methods in terms of performance. Simulated results show that our method is more sensitive than competing methods. Applied to the real data, our method can identify more common DMRs than DMRcate, ProbeLasso, and Wang’s methods with a high overlapping ratio. Also, the necessity of integrating the heterogeneity and correlation characteristics in identifying DMR is shown through comparing results with only considering mean or variance signals and without considering relationship of neighboring CpG sites, respectively. Through analyzing the number of DMRs identified in real data located in different genomic regions, we find that about 90% DMRs are located in CGI which always regulates the expression of genes. It may help us understand the functional effect of DNA methylation on disease.


2021 ◽  
Vol 22 (23) ◽  
pp. 12989
Author(s):  
Witold Józef Światowy ◽  
Hanna Drzewiecka ◽  
Michalina Kliber ◽  
Maria Sąsiadek ◽  
Paweł Karpiński ◽  
...  

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.


Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1911 ◽  
Author(s):  
Lucillia Bezu ◽  
Alejandra Wu Chuang ◽  
Peng Liu ◽  
Guido Kroemer ◽  
Oliver Kepp

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.


2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Sinai Li ◽  
Ping Li ◽  
Weihong Liu ◽  
Juju Shang ◽  
Shenglei Qiu ◽  
...  

Background/Aim. Danhong injection (DHI) is a Chinese patent drug used for relieving cardiovascular diseases. Recent studies have suggested that DNA methylation plays a pivotal role in the maintenance of cardiac fibrosis (CF) in cardiovascular diseases. This study was aimed at identifying the effect and the underlying mechanism of DHI on CF, especially the DNA methylation. Methods. A CF murine model was established by thoracic aortic constriction (TAC). A 28-day daily treatment with or without DHI via intraperitoneal injection was carried out immediately following TAC surgery. The changes in cardiac function, pathology, and fibrosis following TAC were measured by echocardiography and immunostaining. We used methyl-seq analysis to assess the DNA methylation changes in whole genes and identified the methylation changes of two Ras signaling-related genes in TAC mice, including Ras protein activator like-1 (Rasal1) and Ras-association domain family 1 (Rassf1). Next, the methylation status and expression levels of Rasal1 and Rassf1 genes were consolidated by bisulfite sequencing, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and Western blotting, respectively. To determine the underlying molecular mechanism, the expressions of DNA methyltransferases (DNMTs), Tet methylcytosine dioxygenase 3 (TET3), fibrosis-related genes, and the activity of Ras/ERK were measured by RT-qPCR and Western blotting. Results. DHI treatment alleviated CF and significantly improved cardiac function on day 28 of TAC. The methyl-seq analysis identified 42,606 differential methylated sites (DMSs), including 19,618 hypermethylated DMSs and 22,988 hypomethylated DMSs between TAC and sham-operated mice. The enrichment analysis of these DMSs suggested that the methylated regulation of Ras signal transduction and focal adhesion-related genes would be involved in the TAC-induced CF development. The results of bisulfite sequencing revealed that the TAC-induced methylation affected the CpG site in both of Rasal1 and Rassf1 genes, and DHI treatment remarkably downregulated the promoter methylation of Rasal1 and Rassf1 in CF hearts. Furthermore, DHI treatment upregulated the expressions of Rasal1 and Rassf1, inhibited the hyperactivity of Ras/ERK, and decreased the expressions of fibrosis-related genes. Notably, we found that DHI treatment markedly downregulated the expression of DNMT3B in CF hearts, while it did not affect the expressions of DNMT1, DNMT3A, and TET3. Conclusion. Aberrant DNA methylation of Rasal1 and Rassf1 genes was involved in the CF development. DHI treatment alleviated CF, prevented the hypermethylation of Rasal1 and Rassf1, and downregulated DNMT3B expression in CF hearts.


Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1540 ◽  
Author(s):  
Klara Cervena ◽  
Anna Siskova ◽  
Tomas Buchler ◽  
Pavel Vodicka ◽  
Veronika Vymetalkova

Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient’s methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.


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