Browsing by Subject "DNA methylation"
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- PublicationOpen AccessAging, methylation and cancer(2000) Ahuja, N.; Issa, J.-P.J.Alterations in methylation are widespread in cancers. DNA methylation of promoter-associated CpG islands is an alternate mechanism to mutation in silencing gene function, and affects tumor-suppressor genes such as p16 and RBl, growth and differentiation controlling genes such as ER and many others. Evidence is now accumulating that some of these methylation changes may initiate in subpopulations of normal cells as a function of age and progressively increase during carcinogenesis. Age-related methylation appears to be widespread and is one of the earliest changes marking the risk for neoplasia. In colon cancer, we have shown a pattern of age-related methylation for several genes, including ER, IGF2, N33 and MyoD, which progresses to full methylation in adenomas and neoplasms . Hypermethylation of these genes is associated with gene silencing. Age-related methylation involves at least 50% of the genes which are hypermethylated in colon cancer, and we propose that such age-related methylation may partly account for the fact that most cancers occur as a function of old age. Age-related methylation, then, may be a fundamental mark of the field defect in patients with neoplasia. The causes of age-related methylation are still unknown at this point, but evidence points to an interplay between local predisposing factors in DNA (methylation centers), levels of gene expression and environmental exposure. The concept that age-related methylation is a predisposing factor for neoplasia implies that it may serve as a diagnostic risk marker in cancer, and as a novel target for chemoprevention. Studies in animal models support this hypothesis and should lead to novel approaches to risk-assessment and chemoprevention in humans.
- PublicationOpen AccessDNA methylation and gene expression changes derived from assisted reproductive technologies can be decreased by reproductive fluids.(2017) Cánovas Bernabé, Sebastián; Romar Andrés, Raquel; Garcia Martinez, S.; Soriano Ubeda, C. D. L. M.; García Vázquez, Francisco Alberto; Coy Fuster, Pilar; Ivanova, Elena; Saadeh, Heba; Andrews, Simon; Kelsey, Gavin; Fisiología
- PublicationOpen AccessEffect of Superovulation Treatment on Oocyte's DNA Methylation(MDPI, 2022-12-18) S. Lopes, Jordana; Ivanova, Elena; Ruiz, Salvador; Andrews, Simon; Kelsey, Gavin; Coy, Pilar; Didáctica y Organización EscolarControlled ovarian stimulation is a necessary step in some assisted reproductive procedures allowing a higher collection of female gametes. However, consequences of this stimulation for the gamete or the offspring have been shown in several mammals. Most studies used comparisons between oocytes from different donors, which may contribute to different responses. In this work, we use the bovine model in which each animal serves as its own control. DNA methylation profiles were obtained by single-cell whole-genome bisulfite sequencing of oocytes from pre-ovulatory unstimulated follicles compared to oocytes from stimulated follicles. Results show that the global percentage of methylation was similar between groups, but the percentage of methylation was lower for non-stimulated oocytes in the imprinted genes APEG3, MEG3, and MEG9 and higher in TSSC4 when compared to stimulated oocytes. Differences were also found in CGI of imprinted genes: higher methylation was found among non-stimulated oocytes in MEST (PEG1), IGF2R, GNAS (SCG6), KvDMR1 ICR UMD, and IGF2. In another region around IGF2, the methylation percentage was lower for non-stimulated oocytes when compared to stimulated oocytes. Data drawn from this study might help to understand the molecular reasons for the appearance of certain syndromes in assisted reproductive technologies-derived offspring.
- PublicationOpen AccessEffect of superovulation treatment on oocyte´s DNA methylation.(MDPI, 2022-12-18) Lopes, J.S.; Ivanova, E.; Ruiz, S.; Andrews, S.; Kelsey, G.; Coy, P.; Fisiología; Epigenetics Programme. Babraham Institute. Cambridge, U.K.; Bioinformatics Group. Babraham Institute. Cambridge, U.K.; Centre for Trophoblast Research. Cambridge University. U.K.Controlled ovarian stimulation is a necessary step in some assisted reproductive procedures allowing a higher collection of female gametes. However, consequences of this stimulation for the gamete or the offspring have been shown in several mammals. Most studies used comparisons between oocytes from different donors, which may contribute to different responses. In this work, we use the bovine model in which each animal serves as its own control. DNA methylation profiles were obtained by single-cell whole-genome bisulfite sequencing of oocytes from pre-ovulatory unstimulated follicles compared to oocytes from stimulated follicles. Results show that the global percentage of methylation was similar between groups, but the percentage of methylation was lower for non-stimulated oocytes in the imprinted genes APEG3, MEG3, and MEG9 and higher in TSSC4 when compared to stimulated oocytes. Differences were also found in CGI of imprinted genes: higher methylation was found among non-stimulated oocytes in MEST (PEG1), IGF2R, GNAS (SCG6), KvDMR1 ICR UMD, and IGF2. In another region around IGF2, the methylation percentage was lower for non-stimulated oocytes when compared to stimulated oocytes. Data drawn from this study might help to understand the molecular reasons for the appearance of certain syndromes in assisted reproductive technologies-derived offspring.
- PublicationOpen AccessEpigenetic remodelling of DNA in cancer(Murcia: F. Hernández, 2007) Lettini, A.A.; Guidoboni, M.; Fonsatti, E.; Anzalone, L.; Cortini, E.; Maio, M.DNA methylation regulates gene expression in normal cells. This epigenetic mechanism acts in at least two different ways: at global genomic level by targeting repetitive sequences distributed among the whole genome (LINEs, SINEs, satellite DNA, transposons) and at local level by targeting CpG islands in promoter regions. Both epigenetic mechanisms are involved in the carcinogenetic process; however, different evidences suggest that promoter hypermethylation occurring in genes involved in cellcycle regulation, DNA repair, cell signalling, transcription and apoptosis likely plays a prominent role. Opposite to genetic defects DNA hypermethylation is a reversible process that can be handled through “epigenetic drugs” in a wide spectrum of tumors. Along this line, recent data have demonstrated the ability of DNA hypomethylating agents to up-regulate and/or induce the expression of genes silenced by promoter hypermethylation in cancer. Particularly relevant seems the ability of these drugs to modulate the expression of genes coding for molecules crucial for tumor immunogenicity and immune recognition of neoplastic cells by host’s immune system, such as Cancer Testis Antigens, HLA class I molecules, costimulatory molecules. These evidences, coupled to the well-known cytotoxic, pro-apoptotic, and differentiating activities of epigenetic drugs, encourage to design and to develop new therapeutic strategies able to circumvent the immune escape of neoplastic cells and to potentiate the efficacy of immunotherapy in cancer patients. This review will provide an update on the most recent information about aberrant DNA methylation in cancer and on innovative therapeutic strategies of “epigenetic remodelling” of human malignancies, with particular attention to the immunologic and immunotherapeutic potential of this approach.
- PublicationOpen AccessExpression of DNA methylation-related proteins in invasive lobular carcinoma of breast: comparison to invasive ductal carcinoma(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Cha, Yoon Jin; Kim, Hye Min; Koo, Ja SeungPurpose: We aimed to compare the expression of DNA methylation-related proteins in invasive lobular carcinoma (ILC) of breast with those of invasive ductal carcinoma (IDC) of breast and to assess its potential clinical application. Methods: Immunohistochemical staining of DNA methylation-related proteins (5-meC, DNMT1, DNMT3B and ISL-1) was applied to tissue microarrays generated from 108 ILCs and 203 IDCs. Protein expression and its correlation with clinicopatholgic variables were statistically analyzed. Results: ISL-1 and DNMT3B were highly expressed in ILC (p<0.001) and tumoral 5-meC was highly expressed in IDC (p=0.006). DNMT1 (p<0.001) showed higher expression rate in luminal A type ILC. ISL-1 and DNMT3B showed higher expression rate in both luminal A type and luminal B type of ILC (p<0.05). In IDC, tumoral 5-meC commonly showed high positivity (p=0.039). On univariate analysis, shorter disease-free survival of ILC was associated with DNMT1 high positivity (p=0.001) and ISL-1 positivity (p=0.018). Conclusion: DNA methylation-related proteins are differentially expressed in ILC and IDC, and DNMT1, DNMT3B and ISL-1 show high expression rate in ILC.
- PublicationOpen AccessRegulation of DNA methylation levels in the process of oral mucosal regeneration of oral ulcer model.(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Akiyama, Naotaro; Fukuda, Tomomi Yamamoto; Yoshikawa, Mamoru; Kojima, HiromiDNA methylation is an important epigenetic mechanism for cellular maintenance. However, the methylation pattern and the key molecule regulated epigenetically in oral mucosal regeneration is unclear. In this study, we generated a rat oral ulcer model and investigated the cell proliferative activities and DNA methylation patterns immunohistochemically. We also performed immunohistochemical analysis of a regulator of epithelial stem/progenitor cell differentiation in the rat model. We demonstrated immunohistochemistry using antibodies for the molecules as follows: Ki-67, a marker of cellular proliferation; 5-methylcytosine (5-mC), a marker of DNA methylation; 5-hydroxymethylcytosine (5-hmC), a marker of DNA demethylation; Dnmt1, a maintenance DNA methyltransferase; Dnmt3a and Dnmt3b, de novo DNA methyltransferases; and Wnt5a, a regulator of stem/progenitor cell differentiation. In this model, re-epithelialization was completed at Day 4 after ulceration. Regenerating mucosal hypertrophy reached a peak at Day 5 and appeared normal at Day 14. Ki-67-positive cells increased at Day 2 and returned to normal at Day 6 after ulceration. The ratio of the expression level of 5-mC to 5-hmC declined at Day 5 and returned to normal at Day 6. The expression level of Dnmt1 had not changed compared to the normal control at every time point. On the other hand, the expression levels of Dnmt3a and Dnmt3b had decreased significantly at Day 5 and returned to normal at Day 6. Moreover, Wnt5a-positive cells increased at Day 5. In conclusion, oral mucosal regeneration was strictly regulated by DNA methylation. Moreover, Wnt5a might play a critical role in oral mucosal regeneration.
- PublicationOpen AccessSpontaneous and ART-induced large offspring syndrome: similarities and differences in DNA methylome(Taylor and Francis Group, 2022-05-03) Yahan Li; Sena Lopes, Jordana; Coy-Fuster, Pilar; Melissa Rivera, Rocío; Didáctica y Organización EscolarLarge/abnormal offspring syndrome (LOS/AOS) is a congenital overgrowth syndrome reported in ruminants produced by assisted reproduction (ART-LOS) which exhibit global disruption of the epigenome and transcriptome. LOS/AOS shares phenotypes and epigenotypes with the human congenital overgrowth condition Beckwith-Wiedemann syndrome. We have reported that LOS occurs spontaneously (SLOS); however, to date, no study has been conducted to determine if SLOS has the same methylome epimutations as ART-LOS. In this study, we performed whole- genome bisulphite sequencing to examine global DNA methylation in bovine SLOS and ART-LOS tissues. We observed unique patterns of global distribution of differentially methylated regions (DMRs) over different genomic contexts, such as promoters, CpG Islands, shores and shelves, as well as at repetitive sequences. In addition, we included data from two previous LOS studies to identify shared vulnerable genomic loci in LOS. Overall, we identified 320 genomic loci in LOS that have alterations in DNA methylation when compared to controls. Specifically, there are 25 highly vulnerable loci that could potentially serve as molecular markers for the diagnosis of LOS, including at the promoters of DMRT2 and TBX18, at the imprinted gene bodies of IGF2R, PRDM8, and BLCAP/NNAT, and at multiple CpG Islands. We also observed tissue-specific DNA methylation patterns between muscle and blood, and conservation of ART-induced DNA methyla-tion changes between muscle and blood. We conclude that as ART-LOS, SLOS is an epigenetic condition. In addition, SLOS and ART-LOS share similarities in methylome epimutations.