Epigenomes最新文献

{"title":"Genetics and Epigenetics of Chemoinduced Oral Mucositis in Paediatric Patients with Haematological Malignancies-A Review.","authors":"Juliana Ramalho Guimarães, José Maria Chagas Viana Filho, Naila Francis Paulo de Oliveira","doi":"10.3390/epigenomes9020016","DOIUrl":"10.3390/epigenomes9020016","url":null,"abstract":"<p><strong>Background: </strong>Oral mucositis (OM) is a painful inflammation resulting from chemotherapy. It is dependent on factors such as age, gender, chemotherapy regimen, oral health, immunological and nutritional status, and genetics.</p><p><strong>Objectives: </strong>The aim of the study was to conduct a narrative review to compile studies on the contribution of genetic and epigenetic aspects to the pathogenesis of OM in children with haematological malignancies undergoing chemotherapy treatment.</p><p><strong>Methods: </strong>The literature search was performed in Pubmed, Scopus, Web of Science, Cochrane, Lilacs, and grey literature databases covering articles published since 2010.</p><p><strong>Results: </strong>Twenty-two studies investigating polymorphisms and four studies investigating DNA methylation were included. Polymorphisms in the <i>MTHFR</i>, <i>ABCB1</i>, <i>ABCC2</i>, <i>ABCG2</i>, <i>SLCO1B</i>, <i>miR-1206</i>, <i>miR-3683</i>, <i>CAT</i>, and <i>VDR</i> genes were associated as risk factors for OM and polymorphisms in the <i>TYMS</i> and <i>miR-4268</i> genes were associated as protective factors. With regard to DNA methylation, associations such as protection or susceptibility to OM have not yet been proven. However, studies have shown that <i>DNMT1</i> methylation and hypomethylation in total DNA and in the <i>TNF-α</i> gene are associated with recovery of the oral mucosa.</p><p><strong>Conclusions: </strong>Genetic variants are associated with OM in various biological pathways, such as folate metabolism, transport proteins, epigenetic machinery, oxidative stress, and vitamin D metabolism. The DNA methylation profile, which is still poorly understood in the pathogenesis of OM, is associated with mucosal recovery (inflammation and epigenetic machinery). Genetic and epigenetic markers may be tools to indicate a patient's susceptibility to developing OM, and epigenetic markers may be a target for therapies.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12191452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone H3 Lysine 9 Acetylation Plays a Role in Adipogenesis of Periodontal Ligament-Derived Stem Cells.","authors":"Julio A Montero-Del-Toro, Angelica A Serralta-Interian, Geovanny I Nic-Can, Mónica Lamas, Rodrigo A Rivera-Solís, Beatriz A Rodas-Junco","doi":"10.3390/epigenomes9020015","DOIUrl":"10.3390/epigenomes9020015","url":null,"abstract":"<p><strong>Background: </strong>The epigenetic regulation of adipogenic differentiation in dental stem cells (DSCs) remains poorly understood, as research has prioritized osteogenic differentiation for dental applications. However, elucidating these mechanisms could enable novel regenerative strategies for soft tissue engineering. Periodontal ligament stem cells (PDLSCs) exhibit notable adipogenic potential, possibly linked to histone 3 acetylation at lysine 9 (H3K9ac); however, the mechanistic role of this modification remains unclear.</p><p><strong>Methods: </strong>To address this gap, we investigated how histone deacetylase inhibitors (HDACis)-valproic acid (VPA, 8 mM) and trichostatin A (TSA, 100 nM)-modulate H3K9ac dynamics, adipogenic gene expression (<i>C/EBPβ</i> and <i>PPARγ-2</i>), and chromatin remodeling during PDLSCs differentiation. Techniques used included quantitative PCR (qPCR), lipid droplet analysis, and chromatin immunoprecipitation followed by qPCR (ChIP-qPCR).</p><p><strong>Results: </strong>TSA-treated cells exhibited increased lipid deposition with smaller lipid droplets compared to VPA-treated cells. Global H3K9ac levels correlated positively with adipogenic progression. VPA induced early upregulation of <i>C/EBPβ</i> and <i>PPARγ-2</i> (day 7), whereas TSA triggered a delayed but stronger <i>PPARγ-2</i> expression. ChIP-qPCR analysis revealed significant H3K9ac enrichment at the <i>PPARγ-2</i> promoter in TSA-treated cells, indicating enhanced chromatin accessibility.</p><p><strong>Conclusions: </strong>These findings demonstrate that H3K9ac-mediated epigenetic remodeling plays a critical role in the adipogenic differentiation of PDLSCs and identifies TSA as a potential tool for modulating this process.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12192146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discrimination, Coping, and DNAm Accelerated Aging Among African American Mothers of the InterGEN Study.","authors":"Alexandria Nyembwe, Yihong Zhao, Billy A Caceres, Daniel W Belsky, Calen Patrick Ryan, Brittany Taylor, Morgan T Morrison, Laura Prescott, Stephanie Potts-Thompson, Arezo Aziz, Fisola Aruleba, Erica Matute-Arcos, Olajide Williams, Cindy Crusto, Jacquelyn Y Taylor","doi":"10.3390/epigenomes9020014","DOIUrl":"10.3390/epigenomes9020014","url":null,"abstract":"<p><p><b>Background:</b> Racial discrimination experiences are associated with the activation of stress biology pathways and signs of accelerated biological aging, including alterations in DNA methylation (DNAm). Coping strategies may mitigate stress from racial discrimination and protect against long-term adverse health outcomes. <b>Methods:</b> We conducted a secondary analysis of data from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure cohort, an all-African-American sample, to test the hypothesis that social support can protect against accelerated biological aging associated with experiences of racial discrimination. We measured biological aging from saliva DNAm using six epigenetic clocks. Clock values were residualized on participant age and the estimated proportion of epithelial cells contributing to the DNA sample and standardized to M = 0, SD = 1 within the analysis sample. The primary analysis was focused on the second-generation PhenoAge and GrimAge clocks and the third-generation DunedinPACE \"speedometer,\" which previous studies have linked with racial discrimination. <b>Results:</b> In our sample (<i>n</i> = 234; mean age = 31.9 years; SD = 5.80), we found evidence consistent with our hypothesis in the case of the PhenoAge clock, but not the other clocks. Among mothers who did not seek social support, experiences of racial discrimination were associated with an older PhenoAge (b = 0.26, 95% CI = 0.02-0.50, <i>p</i> = 0.03). However, social-support seeking mitigated this risk; at the highest levels of social support, no adverse consequences of discrimination were observed (interaction b = -0.01, 95% CI = -0.02--0.00, <i>p</i> = 0.03). <b>Conclusions:</b> The replication of results is needed. Future research should also investigate additional adaptive and maladaptive coping strategies utilized by African American women and mothers to identify protective measures that influence health outcomes.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Arabidopsis thaliana</i> Roots Exposed to Extracellular Self-DNA: Evidence of Epigenetic Effects.","authors":"Alessia Ronchi, Guido Incerti, Emanuele De Paoli, Speranza Claudia Panico, Giovanni Luca Sciabbarrasi, Pasquale Termolino, Fabrizio Cartenì, Mariachiara Langella, Maria Luisa Chiusano, Stefano Mazzoleni","doi":"10.3390/epigenomes9020013","DOIUrl":"10.3390/epigenomes9020013","url":null,"abstract":"<p><strong>Background: </strong>Previous evidence demonstrated DNA methylation changes in response to stress in plants, showing rapid changes within a limited time frame. Exposure to self-DNA inhibits seedling root elongation, and it was shown that it causes changes in CG DNA methylation in <i>Lactuca sativa</i>. We assessed cytosine methylation changes and associated gene expression patterns in roots of <i>Arabidopsis thaliana</i> Col-0 seedlings exposed to self-DNA for 6 and 24 h.</p><p><strong>Methods: </strong>We used whole genome bisulfite sequencing (WGBS) and RNA-seq analyses to assess genomic cytosine methylation and corresponding gene expression, respectively, on DNA and RNA extracted with commercial kits from roots exposed to self-DNA by an original setup. Fifteen hundred roots replicates, including the control in distilled water, were collected after exposure. Sequencing was performed on a NovaSeq 6000 platform and Ultralow Methyl-Seq System for RNA and DNA WGBS, respectively.</p><p><strong>Results: </strong>Gene expression in roots exposed to self-DNA differed from that of untreated controls, with a total of 305 genes differentially expressed and 87 ontologies enriched in at least one treatment vs. control comparison, and particularly after 24 h of exposure. DNA methylation, particularly in CHG and CHH contexts, was also different, with hyper- and hypomethylation prevailing in treatments vs. controls at 6 h and 24 h, respectively. Differentially expressed genes (DEGs) analysis, Gene Ontology (GO) enrichment analysis, and differentially methylated regions (DMRs) analysis, provided an integrated understanding of the changes associated with self-DNA exposure. Our results suggest differential gene expression associated with DNA methylation in response to self-DNA exposure in <i>A. thaliana</i> roots, enhanced after prolonged exposure.</p><p><strong>Conclusions: </strong>Main functional indications of association between DNA methylation and gene expression involved hypomethylation and downregulation of genes related to nucleotide/nucleoside metabolism (ATP synthase subunit) and cell wall structure (XyG synthase), consistent with previous observations from metabolomics and physiological studies. Further confirmation of these findings will contribute to improving our understanding of the plant molecular response to self-DNA and its implications in stress responses.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of Clinical Factors on the Reversion of Cg05575921 Methylation in Smoking Cessation.","authors":"Robert Philibert, Steven R H Beach, Michelle R vanDellen, James A Mills, Jeffrey D Long","doi":"10.3390/epigenomes9020012","DOIUrl":"10.3390/epigenomes9020012","url":null,"abstract":"<p><strong>Background: </strong>Financial Incentive Treatments (FIT) can be effective in the treatment of smoking. However, weaknesses in current biochemical approaches for assessing smoking cessation may hinder its implementation, particularly for management of long-term smoking cessation. The use of cg05575921 methylation assessments could address some of the shortcomings of current self-report and non-self-report methods, but additional information is needed about the speed of methylation reversion as a function of key clinical and demographic variables.</p><p><strong>Methods: </strong>To better understand those relationships, we analyzed data from 3040 subjects from the National Lung Screening Trial (NLST), including 1552 self-reported quitters.</p><p><strong>Results: </strong>Plotting of the data as a function of time since quitting shows that methylation increases approximately 14%, on average, after at least one full year of cessation with a subsequent slow non-linear increase in methylation over the next 14 years. Least Squares Regression modeling shows strong effects of quit time and a modest, yet significant, effect of body mass index (BMI) on the rate of reversion. Prior cigarette consumption characteristics and sex made modest contributions as well, with the latter largely offset by pre-cessation methylation levels. Race and age were not significant factors in the models.</p><p><strong>Conclusions: </strong>When combined with data from prior studies, these analyses of the long-term reversion of cg05575921 methylation will be informative to those considering FIT approaches to incentivizing reversion of cg05575921 as an index of short- and long-term smoking cessation.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction of DNA Demethylation: Strategies and Consequences.","authors":"Pietro Salvatore Carollo, Viviana Barra","doi":"10.3390/epigenomes9020011","DOIUrl":"https://doi.org/10.3390/epigenomes9020011","url":null,"abstract":"<p><p>DNA methylation is an important epigenetic modification with a plethora of effects on cells, ranging from the regulation of gene transcription to shaping chromatin structure. Notably, DNA methylation occurs thanks to the activity of DNA methyltransferases (DNMTs), which covalently add a methyl group to the cytosine in position 5' in CpG dinucleotides. Different strategies have been developed to study the effects of DNA methylation in cells, involving either DNMTs inhibition (passive DNA demethylation) or the use of Ten-eleven translocation protein (TET) family enzymes, which directly demethylate DNA (active DNA demethylation). In this manuscript, we will briefly cover the most commonly used strategies in the last two decades to achieve DNA demethylation, along with their effects on cells. We will also discuss some of the newest inducible ways to inhibit DNMTs without remarkable side effects, as well as the effect of non-coding RNAs on DNA methylation. Lastly, we will briefly examine the use of DNA methylation inhibition in biomedical research.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Good, the Bad, and the Epigenetic: Stress-Induced Metabolite Regulation and Transgenerational Effects.","authors":"Saida Ibragić, Sabina Dahija, Erna Karalija","doi":"10.3390/epigenomes9020010","DOIUrl":"https://doi.org/10.3390/epigenomes9020010","url":null,"abstract":"<p><strong>Background: </strong>Plants face a wide range of environmental stresses that disrupt growth and productivity. To survive and adapt, they undergo complex metabolic reprogramming by redirecting carbon and nitrogen fluxes toward the biosynthesis of protective secondary metabolites such as phenylpropanoids, flavonoids, and lignin. Recent research has revealed that these stress-induced metabolic processes are tightly regulated by epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs.</p><p><strong>Methods: </strong>This review synthesizes current findings from studies on both model and crop plants, examining the roles of key epigenetic regulators in controlling secondary metabolism under stress. Special focus is placed on dynamic changes in DNA methylation, histone acetylation, and the action of small RNAs such as siRNAs and miRNAs in transcriptional and post-transcriptional regulation.</p><p><strong>Results: </strong>Evidence indicates that stress triggers rapid and reversible epigenetic modifications that modulate gene expression linked to secondary metabolic pathways. These modifications not only facilitate immediate metabolic responses but can also contribute to stress memory. In some cases, this memory is retained and transmitted to the next generation, influencing progeny stress responses. However, critical knowledge gaps remain, particularly concerning the temporal dynamics, tissue specificity, and long-term stability of these epigenetic marks in crops.</p><p><strong>Conclusions: </strong>Understanding how epigenetic regulation governs secondary metabolite production offers promising avenues to enhance crop resilience and productivity in the context of climate change. Future research should prioritize dissecting the stability and heritability of these modifications to support the development of epigenetically informed breeding strategies.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Association of Childhood Allergic Diseases with Prenatal Exposure to Pollen Grains Through At-Birth DNA Methylation.","authors":"Rajesh Melaram, Hongmei Zhang, James Adefisoye, Hasan Arshad","doi":"10.3390/epigenomes9010009","DOIUrl":"10.3390/epigenomes9010009","url":null,"abstract":"<p><strong>Background: </strong>Pollen exposure in early life is shown to be associated with allergy and asthma. DNA methylation (DNAm), an epigenetic marker, potentially reacts to pollen. However, the role of at-birth DNAm between prenatal pollen grain (PPG) exposure and childhood asthma and allergic rhinitis is unknown.</p><p><strong>Methods: </strong>Data in a birth cohort study on the Isle of Wight, UK, were analyzed (<i>n</i> = 236). Newborn DNAm was measured in cord blood or blood spots on Guthrie cards and screened for potential association with PPG exposure using the R package ttScreening. CpGs that passed screening were further assessed for such associations via linear regressions with adjusting covariates included. Finally, DNAm at PPG-associated CpGs were evaluated for their association with asthma and allergic rhinitis using logistic regressions, adjusting for covariates. The impact of cell heterogeneity on the findings was assessed. Statistical significance was set at <i>p</i> < 0.05.</p><p><strong>Results: </strong>In total, 42 CpGs passed screening, with 41 remaining statistically significant after adjusting for covariates and cell types (<i>p</i> < 0.05). High PPG exposure was associated with lower DNAm at cg12318501 (<i>ZNF99</i>, β = -0.029, <i>p</i> = 0.032) and cg00929606 (<i>ADM2</i>, β = -0.023, <i>p</i> = 0.008), which subsequently was associated with decreased odds of asthma (OR = 0.11, 95% CI 0.02-0.53, <i>p</i> = 0.006; OR = 0.14, 95% CI 0.02-1.00, <i>p</i> = 0.049). For rhinitis, cg15790214 (<i>HCG11</i>) was shown to play such a role as a mediator (β = -0.027, <i>p</i> ≤ 0.0001; OR = 0.22, 95% CI 0.07-0.72, <i>p</i> = 0.01).</p><p><strong>Conclusions: </strong>The association of PPG exposure with childhood asthma and allergic rhinitis incidence is potentially mediated by DNAm at birth.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating Single-Molecule Molecular Inversion Probes for Medium-Scale Targeted DNA Methylation Analysis.","authors":"Roy B Simons, Hieab H H Adams, Manfred Kayser, Athina Vidaki","doi":"10.3390/epigenomes9010008","DOIUrl":"10.3390/epigenomes9010008","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic biomarkers, particularly CpG methylation, are increasingly employed in clinical and forensic settings. However, we still lack a cost-effective, sensitive, medium-scale method for the analysis of hundreds to thousands of user-defined CpGs suitable for minute DNA input amounts (<10 ng). In this study, motivated by promising results in the genetics field, we investigated single-molecule molecular inversion probes (smMIPs) for simultaneous analysis of hundreds of CpGs by using an example set of 514 age-associated CpGs (Zhang model).</p><p><strong>Methods: </strong>First, we developed a novel smMIP design tool to suit bisulfite-converted DNA (Locksmith). Then, to optimize the capture process, we performed single-probe capture for ten selected, representative smMIPs. Based on this pilot, the full smMIP panel was tested under varying capture conditions, including hybridization and elongation temperature, smMIP and template DNA amounts, dNTP concentration and elongation time.</p><p><strong>Results: </strong>Overall, we found that the capture efficiency was highly probe-(and hence, sequence-) dependent, with a heterogeneous coverage distribution across CpGs higher than the 1000-fold range. Considering CpGs with at least 20X coverage, we yielded robust methylation detection with levels comparable to those obtained from the gold standard EPIC microarray analysis (Pearsons's r: 0.96).</p><p><strong>Conclusions: </strong>The observed low specificity and uniformity indicate that smMIPs in their current form are not compatible with the lowered complexity of bisulfite-converted DNA.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11941031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isothiocyanates Enhance the Anti-Melanoma Effect of Zebularine Through Modulation of Apoptosis and Regulation of DNMTs' Expression, Chromatin Configuration and Histone Posttranslational Modifications Associated with Altered Gene Expression Patterns.","authors":"Ioannis Anestopoulos, Ioannis Paraskevaidis, Sotiris Kyriakou, Louiza Potamiti, Dimitrios T Trafalis, Sotiris Botaitis, Rodrigo Franco, Aglaia Pappa, Mihalis I Panayiotidis","doi":"10.3390/epigenomes9010007","DOIUrl":"10.3390/epigenomes9010007","url":null,"abstract":"<p><p><b>Background:</b> In the present study, we aimed to characterize the cytotoxic efficacy of Zebularine either as a single agent or in combination with various isothiocyanates in an in vitro model consisting of human melanoma (A375, Colo-679) as well as non-tumorigenic immortalized keratinocyte (HaCaT) cells. <b>Methods:</b> In this model, we have evaluated the anti-melanoma effect of Zebularine (in single and combinatorial protocols) in terms of cell viability, apoptotic induction and alterations in ultrastructural chromatin configuration, protein expression levels of DNA methyltransferases (DNMTs) and associated histone epigenetic marks capable of mediating gene expression. <b>Results:</b> Exposure to Zebularine resulted in dose- and time-dependent cytotoxicity through apoptotic induction in malignant melanoma cells, while neighboring non-tumorigenic keratinocytes remained unaffected. A more profound response was observed in combinational protocols, as evidenced by a further decline in cell viability leading to an even more robust apoptotic induction followed by a differential response (i.e., activation/de-activation) of various apoptotic genes. Furthermore, combined exposure protocols caused a significant decrease of DNMT1, DNMT3A and DNMT3B protein expression levels together with alterations in ultrastructural chromatin configuration and protein expression levels of specific histone modification marks capable of modulating gene expression. <b>Conclusions:</b> Overall, we have developed a novel experimental approach capable of potentiating the cytotoxic efficacy of Zebularine against human malignant melanoma cells while at the same time maintaining a non-cytotoxic profile against neighboring non-tumorigenic keratinocyte (HaCaT) cells.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"9 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11941220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}