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1.
Anticancer Res ; 40(1): 201-211, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892568

RESUMO

BACKGROUND/AIM: This retrospective study focused on the correlation between molecular markers and prognostic outcomes of colon cancer patients depending on sidedness. MATERIALS AND METHODS: A total of 117 stage I-III colon cancer patients who underwent colectomy were enrolled. Novel methylation markers (KIF1A, PAX5 and VGF) were selected for epigenetic evaluation and p53 and ERCC1 protein expression was examined for the investigation of genetic alterations. RESULTS: High frequency of methylation was observed in 68.2% of right-sided and 39.7% of left-sided colon cancer cases (p=0.004). Abnormal p53 was identified in 52.3% of right-sided and 75.3% of left-sided cases (p=0.015). In right-sided cases, highly methylated genes demonstrated significantly favorable disease-free survival (p=0.049). Regarding left-sided cases, advanced T stage (p=0.028) and abnormal p53 (p=0.028) were revealed to be significant predictive factors of the disease-free survival outcome. CONCLUSION: Molecular alterations, as significant prognostic factors, might differ depending on the sidedness of colon cancers.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Idoso , Metilação de DNA/genética , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Análise Multivariada , Proteínas de Neoplasias/metabolismo , Curva ROC , Análise de Sobrevida
2.
Medicine (Baltimore) ; 98(38): e17225, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567982

RESUMO

The present study is to analyze the difference of gene methylation in early cervical adenocarcinoma and to find molecular markers for predicting the occurrence and development of cervical adenocarcinoma.A total of 15 cases of primary cervical adenocarcinoma and 10 cases of primary cervical squamous cell carcinoma at stages IB1 or IIA1 were included in the study. Infinium MethylationEPIC BeadChip (850K) was used to screen specifically expressed genes in cervical adenocarcinoma tissues. Bisulfite sequencing polymerase chain reaction (BSP) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to verify the methylation levels in cervical adenocarcinoma, cervical squamous cell carcinoma, and normal cervical tissues.Sex determining region Y-box 1 (SOX1) and cyclin D1 (CCND1) genes participated in multiple signaling pathways, being the central nodes of gene regulatory networks. SOX1 gene, but not CCND1 gene, was a specifically methylated gene in cervical adenocarcinoma according to BSP. According to qRT-PCR, methylation level of SOX1 in cervical adenocarcinoma tissues is significantly different from that in cervical squamous cell carcinoma tissues or normal cervical tissues, and the methylation level of CCND1 in cervical adenocarcinoma tissues or cervical squamous cell carcinoma tissues is significantly different from that in normal cervical tissues.The present study demonstrates that tumor-suppressor gene SOX1 is a methylation-specific expression gene of cervical adenocarcinoma and is expected to become a specific molecular marker for the diagnosis of cervical adenocarcinoma. However, CCND1 gene was not proven to be a specific methylation expression gene in cervical adenocarcinoma in the present study.


Assuntos
Adenocarcinoma/genética , Metilação de DNA/genética , Fatores de Transcrição SOXB1/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Colo do Útero/metabolismo , Ciclina D1/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/genética , Marcadores Genéticos/genética , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias do Colo do Útero/metabolismo
3.
Anticancer Res ; 39(10): 5361-5367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570430

RESUMO

BACKGROUND/AIM: The mechanism responsible for B-cell translocation gene 1 (BTG1) down-regulation in breast carcinoma remains unknown. We examined the BTG1 expression status in breast carcinoma cells and investigated the mechanism underlying the observed alterations. MATERIALS AND METHODS: Four breast carcinoma cell lines (SK-BR-3, MDA-MB-231, T-47D, and MCF-7), and one normal mammary epithelial cell line (MCF-10A) were analyzed. BTG1 expression was examined using quantitative reverse transcription polymerase chain reaction (PCR) and western blot. Methylation status of the BTG1 promoter was analyzed using methylation-specific PCR (MSP). To investigate the effect of methylation on BTG1, the cells were treated with a demethylating agent. RESULTS: The carcinoma cells expressed significantly lower levels of BTG1 mRNA and protein than normal cells. The BTG1 promoter was highly methylated in the carcinoma cells. 5-aza-2-deoxycytidine significantly restored BTG1 expression. CONCLUSION: Down-regulation of BTG1 expression through epigenetic repression is involved in mammary carcinogenesis. BTG1 is a potential diagnostic marker and therapeutic target for breast carcinoma.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA/genética , Regulação para Baixo/genética , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Epigênese Genética/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , RNA Mensageiro/genética
4.
Anticancer Res ; 39(10): 5381-5391, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570433

RESUMO

BACKGROUND/AIM: Long noncoding RNAs (lncRNAs) are noncoding transcripts that are >200 nucleotides in length. However, the biological functions and regulation mechanisms of lncRNAs in gastric carcinogenesis remain unknown. MATERIALS AND METHODS: The expression levels of Linc00472 were analyzed by real-time PCR. The DNA methylation status was assessed using Combined Bisulfite Restriction Analysis (COBRA). The biological role of Linc00472 was assessed in AGS cells with Linc00472 overexpression. RESULTS: Using the next-generation sequencing approach, we identified DNA methylation-associated lncRNAs in gastric cancer cells. Among them, the expression level of Linc00472 significantly decreased in gastric cancer tissues compared to adjacent normal tissues. Furthermore, we observed a more frequent hypermethylation of CpG islands upstream of Linc00472 in gastric cancer tissues. Ectopic Linc00472 expression could significantly inhibit gastric cancer cell growth and migration. CONCLUSION: Epigenetically regulated Linc00472 expression plays a crucial role in modulating gastric cancer cell growth and motility.


Assuntos
Metilação de DNA/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ilhas de CpG/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos
5.
Anticancer Res ; 39(10): 5449-5459, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570439

RESUMO

BACKGROUND/AIM: Epigenetic abnormalities in microRNAs (miRNAs) have not been analyzed in samples other than pancreaticobiliary tissues in patients with pancreaticobiliary cancer (PBC). To identify miRNAs specific for PBC, the present study analyzed the methylation of tumor-suppressive miRNAs in bile from patients with pancreaticobiliary diseases. MATERIALS AND METHODS: Bile was collected endoscopically or percutaneously from 52 patients with pancreatic cancer, 26 with biliary tract cancer, and 20 with benign pancreaticobiliary diseases. Sequences encoding 16 tumor-suppressive miRNAs were amplified by polymerase chain reaction and sequenced, and their methylation rates were determined. RESULTS: The methylation rates of miR-1247 and miR-200a were significantly higher in patients with pancreatic cancer, and biliary tract cancer than in those with benign diseases, and the methylation rate of miR-200b was significantly higher in patients with pancreatic cancer than in those with benign diseases. CONCLUSION: Methylation of miR-1247, miR-200a, and miR-200b in bile may be useful for distinguishing PBC from benign diseases.


Assuntos
Neoplasias do Sistema Biliar/genética , Metilação de DNA/genética , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Bile/metabolismo , Epigenômica/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
6.
Ideggyogy Sz ; 72(9-10): 325-336, 2019 Sep 30.
Artigo em Húngaro | MEDLINE | ID: mdl-31625699

RESUMO

With the acceptance of "The developmental origins of health and disease" concept in the 1990s, it became clear that epigenetic inheritance, which do not involve changes in the DNA sequence has important role in the pathogenesis of diseases. Epigenetic regulation serves the adaptation to the changing environment and maintains the reproductive fitness even on the drawback of increased risk of diseases in later life. The role of epigenetic mechanisms in chronic non-communicable diseases has been well established. Recent studies have revealed that epigenetic changes have also causal role in certain pediatric diseases. The review evaluates the recent epigenetic findings in the pathomechanism of common pediatric diseases. The wide range and long-lasting duration of epigenetic regulations give importance to the subject. Methods are already available to evaluate a part of the epigenetic changes in the clinical practice, presently aiming primarily the estimation of the disease risk or definition of diagnosis. Furthermore, there are already available limited means to influence the epigenetic regulation.


Assuntos
Metilação de DNA/fisiologia , Epigênese Genética , Cardiopatias , Transtornos Mentais , Doenças Metabólicas , Efeitos Tardios da Exposição Pré-Natal , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Cardiopatias/genética , Humanos , Transtornos Mentais/genética , Doenças Metabólicas/genética , Pediatria , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
7.
Medicine (Baltimore) ; 98(43): e17578, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651862

RESUMO

BACKGROUND: To evaluate the methylation levels of human telomerase reverse transcriptase (hTERT) promoter three CpG island (CGIs) regions and its prognostic impact in Chinese patients with acral and mucosal melanoma. METHODS: Bioinformatics software was used to analyze hTERT gene promoter. Fresh frozen tissues were taken from 14 patients with melanoma (6 acral melanoma and 8 mucosal melanoma) and 14 pigmented nevus as control subjects (14 acral pigmented nevus). Bisulfite sequencing PCR (BSP) combined TA clone sequencing was used to assess the methylation levels of hTERT promoter CGIs regions. The relative expression level of hTERT mRNA was measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: CGIs-1 (-1392--1098 bp), CGIs-2 (-945--669 bp), and CGIs-3 (-445--48 bp) were selected for our study. Our results indicated that the methylation levels of hTERT promotor CGIs regions in melanoma were greater than pigmented nevus (CGIs-1: 69.3 ±â€Š18.7% vs 46.8 ±â€Š20.4%, t = 3.048 P = .005; CGIs-2: 73.8 ±â€Š14.7% vs 55.6 ±â€Š16.0%, t = 3.120 P = .004; CGIs-3: 5.8 ±â€Š2.2% vs 2.2 ±â€Š1.3%, t = 5.164 P < .001). The relative expression level of hTERT in melanoma was greater than in pigmented nevus (50.39 ±â€Š9.16 vs 26.10 ±â€Š7.25, t = 7.778, P < .001). Linear regression analysis showed that the methylation level of CGIs-2 in melanoma was positively correlated with the relative expression level of hTERT mRNA (R = .490, F = 13.478, P = .003). Combined with the analysis of clinicopathological features, the methylation level of CGIs-2 in melanoma with lymph node metastasis was greater than in melanoma without lymph node metastasis, and the methylation level of CGIs-2 increased with TNM staging. CONCLUSION: CGIs-2 methylation level was associated with the relative expression level of hTERT mRNA, lymph node metastasis and TNM staging, suggesting that CGIs-2 hypermethylation might be used to evaluate the prognosis in Chinese patients with acral and mucosal melanoma.


Assuntos
Ilhas de CpG/genética , Metilação de DNA/genética , Melanoma/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Telomerase/metabolismo , Idoso , Grupo com Ancestrais do Continente Asiático/genética , China , Biologia Computacional , Feminino , Humanos , Modelos Lineares , Metástase Linfática , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , RNA Mensageiro/metabolismo
8.
BMC Bioinformatics ; 20(1): 462, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500564

RESUMO

BACKGROUND: Determining the association between tumor sample and the gene is demanding because it requires a high cost for conducting genetic experiments. Thus, the discovered association between tumor sample and gene further requires clinical verification and validation. This entire mechanism is time-consuming and expensive. Due to this issue, predicting the association between tumor samples and genes remain a challenge in biomedicine. RESULTS: Here we present, a computational model based on a heat diffusion algorithm which can predict the association between tumor samples and genes. We proposed a 2-layered graph. In the first layer, we constructed a graph of tumor samples and genes where these two types of nodes are connected by "hasGene" relationship. In the second layer, the gene nodes are connected by "interaction" relationship. We applied the heat diffusion algorithms in nine different variants of genetic interaction networks extracted from STRING and BioGRID database. The heat diffusion algorithm predicted the links between tumor samples and genes with mean AUC-ROC score of 0.84. This score is obtained by using weighted genetic interactions of fusion or co-occurrence channels from the STRING database. For the unweighted genetic interaction from the BioGRID database, the algorithms predict the links with an AUC-ROC score of 0.74. CONCLUSIONS: We demonstrate that the gene-gene interaction scores could improve the predictive power of the heat diffusion model to predict the links between tumor samples and genes. We showed the efficient runtime of the heat diffusion algorithm in various genetic interaction network. We statistically validated our prediction quality of the links between tumor samples and genes.


Assuntos
Algoritmos , Genes Neoplásicos , Neoplasias/genética , Área Sob a Curva , Metilação de DNA/genética , Bases de Dados Factuais , Difusão , Epistasia Genética , Redes Reguladoras de Genes , Humanos , Curva ROC , Reprodutibilidade dos Testes
9.
BMC Bioinformatics ; 20(1): 431, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426747

RESUMO

BACKGROUND: Protein pulldown using Methyl-CpG binding domain (MBD) proteins followed by high-throughput sequencing is a common method to determine DNA methylation. Algorithms have been developed to estimate absolute methylation level from read coverage generated by affinity enrichment-based techniques, but the most accurate one for MBD-seq data requires additional data from an SssI-treated Control experiment. RESULTS: Using our previous characterizations of Methyl-CpG/MBD2 binding in the context of an MBD pulldown experiment, we build a model of expected MBD pulldown reads as drawn from SssI-treated DNA. We use the program BayMeth to evaluate the effectiveness of this model by substituting calculated SssI Control data for the observed SssI Control data. By comparing methylation predictions against those from an RRBS data set, we find that BayMeth run with our modeled SssI Control data performs better than BayMeth run with observed SssI Control data, on both 100 bp and 10 bp windows. Adapting the model to an external data set solely by changing the average fragment length, our calculated data still informs the BayMeth program to a similar level as observed data in predicting methylation state on a pulldown data set with matching WGBS estimates. CONCLUSION: In both internal and external MBD pulldown data sets tested in this study, BayMeth used with our modeled pulldown coverage performs better than BayMeth run without the inclusion of any estimate of SssI Control pulldown, and is comparable to - and in some cases better than - using observed SssI Control data with the BayMeth program. Thus, our MBD pulldown alignment model can improve methylation predictions without the need to perform additional control experiments.


Assuntos
Biologia Computacional/métodos , Metilação de DNA/genética , DNA-Citosina Metilases/metabolismo , DNA/metabolismo , Modelos Biológicos , Alinhamento de Sequência , Algoritmos , Pareamento de Bases , Cromossomos Humanos Par 7/genética , Ilhas de CpG/genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Domínio de Ligação a CpG Metilada , Análise de Sequência de DNA/métodos
10.
BMC Bioinformatics ; 20(1): 428, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419933

RESUMO

BACKGROUND: With the advent of array-based techniques to measure methylation levels in primary tumor samples, systematic investigations of methylomes have widely been performed on a large number of tumor entities. Most of these approaches are not based on measuring individual cell methylation but rather the bulk tumor sample DNA, which contains a mixture of tumor cells, infiltrating immune cells and other stromal components. This raises questions about the purity of a certain tumor sample, given the varying degrees of stromal infiltration in different entities. Previous methods to infer tumor purity require or are based on the use of matching control samples which are rarely available. Here we present a novel, reference free method to quantify tumor purity, based on two Random Forest classifiers, which were trained on ABSOLUTE as well as ESTIMATE purity values from TCGA tumor samples. We subsequently apply this method to a previously published, large dataset of brain tumors, proving that these models perform well in datasets that have not been characterized with respect to tumor purity . RESULTS: Using two gold standard methods to infer purity - the ABSOLUTE score based on whole genome sequencing data and the ESTIMATE score based on gene expression data- we have optimized Random Forest classifiers to predict tumor purity in entities that were contained in the TCGA project. We validated these classifiers using an independent test data set and cross-compared it to other methods which have been applied to the TCGA datasets (such as ESTIMATE and LUMP). Using Illumina methylation array data of brain tumor entities (as published in Capper et al. (Nature 555:469-474,2018)) we applied this model to estimate tumor purity and find that subgroups of brain tumors display substantial differences in tumor purity. CONCLUSIONS: Random forest- based tumor purity prediction is a well suited tool to extrapolate gold standard measures of purity to novel methylation array datasets. In contrast to other available methylation based tumor purity estimation methods, our classifiers do not need a priori knowledge about the tumor entity or matching control tissue to predict tumor purity.


Assuntos
Algoritmos , Metilação de DNA/genética , Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Software , Neoplasias Encefálicas/genética , DNA de Neoplasias , Humanos , Reprodutibilidade dos Testes
11.
Aquat Toxicol ; 215: 105272, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442592

RESUMO

A number of chemicals have been shown to affect epigenetic patterning and functions. Since epigenetic mechanisms regulate transcriptional networks, epigenetic changes induced by chemical exposure can represent early molecular events for long-term adverse physiological effects. Epigenetics has thus appeared as a research field of major interest within (eco)toxicological sciences. The present study aimed at measuring effects on epigenetic-related mechanisms of selected environmental chemicals (bisphenols, perfluorinated chemicals, methoxychlor, permethrin, vinclozolin and coumarin 47) in zebrafish embryos and liver cells (ZFL). Transcription of genes related to DNA methylation and histone modifications was measured and global DNA methylation was assessed in ZFL cells using the LUMA assay. The differences in results gathered from both models suggest that chemicals affect different mechanisms related to epigenetics in embryos and cells. In zebrafish embryos, exposure to bisphenol A, coumarin 47, methoxychlor and permethrin lead to significant transcriptional changes in epigenetic factors suggesting that they can impact early epigenome reprogramming related to embryonic development. In ZFL cells, significant transcriptional changes were observed upon exposure to all chemicals but coumarin 47; however, only perfluorooctane sulfonate induced significant effects on global DNA methylation. Notably, in contrast to the other tested chemicals, perfluorooctane sulfonate affected only the expression of the histone demethylase kdm5ba. In addition, kdm5ba appeared as a sensitive gene in zebrafish embryos as well. Taken together, the present results suggest a role for kdm5ba in regulating epigenetic patterns in response to chemical exposure, even though mechanisms remain unclear. To confirm these findings, further evidence is required regarding changes in site-specific histone marks and DNA methylation together with their long-term effects on physiological outcomes.


Assuntos
Embrião não Mamífero/metabolismo , Epigênese Genética , Fígado/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Embrião não Mamífero/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/efeitos dos fármacos , Testes de Toxicidade Aguda , Transcrição Genética/efeitos dos fármacos
12.
Nucleic Acids Res ; 47(18): 9637-9657, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31410472

RESUMO

Establishing causal relationship between epigenetic marks and gene transcription requires molecular tools, which can precisely modify specific genomic regions. Here, we present a modular and extensible CRISPR/dCas9-based toolbox for epigenetic editing and direct gene regulation. It features a system for expression of orthogonal dCas9 proteins fused to various effector domains and includes a multi-gRNA system for simultaneous targeting dCas9 orthologs to up to six loci. The C- and N-terminal dCas9 fusions with DNMT3A and TET1 catalytic domains were thoroughly characterized. We demonstrated simultaneous use of the DNMT3A-dSpCas9 and TET1-dSaCas9 fusions within the same cells and showed that imposed cytosine hyper- and hypo-methylation altered level of gene transcription if targeted CpG sites were functionally relevant. Dual epigenetic manipulation of the HNF1A and MGAT3 genes, involved in protein N-glycosylation, resulted in change of the glycan phenotype in BG1 cells. Furthermore, simultaneous targeting of the TET1-dSaCas9 and VPR-dSpCas9 fusions to the HNF1A regulatory region revealed strong and persistent synergistic effect on gene transcription, up to 30 days following cell transfection, suggesting involvement of epigenetic mechanisms in maintenance of the reactivated state. Also, modulation of dCas9 expression effectively reduced off-target effects while maintaining the desired effects on target regions.


Assuntos
Sistemas CRISPR-Cas/genética , Epigênese Genética , Edição de Genes/métodos , Transcrição Genética , Aciltransferases/genética , Domínio Catalítico/genética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Genoma/genética , Glicosilação , Fator 1-alfa Nuclear de Hepatócito/genética , Humanos , Oxigenases de Função Mista/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , RNA Guia/genética
13.
Anticancer Res ; 39(8): 4003-4010, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366481

RESUMO

Epstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is classified as one of four GC subtypes by comprehensive molecular characterization. Though the mechanism of tumorigenesis by EBV infection has not yet been fully clarified, EBV infection might contribute to the malignant transformation of GC cells by involving various cellular processes and signaling pathways. EBVaGC has shown the following distinct characteristics in contrast to other subtypes: extreme DNA hypermethylation, recurrent phosphatidylinositol 4,5-biphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) mutations, overexpression of programmed cell death ligand 1/2 (PD-L1/2), and occasional immune cell signaling activation. Therefore, using these molecular features as guides, targeted agents need to be evaluated in clinical trials for EBVaGC. Accordingly, this review uses the best available evidence to focus on novel therapeutic approaches using the distinct pathologic characteristics of EBVaGC patients.


Assuntos
Carcinogênese/genética , Infecções por Vírus Epstein-Barr/terapia , Neoplasias Gástricas/terapia , Classe I de Fosfatidilinositol 3-Quinases/genética , Metilação de DNA/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/virologia
14.
Anticancer Res ; 39(8): 4129-4136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366497

RESUMO

BACKGROUND/AIM: 5-Aza-2-deoxycytidine (5-Aza-CdR) enhances the sensitivity to 5-fluorouracil (5-FU), but the molecular mechanism is not fully understood. The aim of this study was to investigate the molecular mechanism that enhances the sensitivity to 5-FU treated with 5-Aza-CdR via thymidine phosphorylase (TP). MATERIALS AND METHODS: The sensitivity to drugs was determined on several cancer cell lines by the MTT assay. Protein and mRNA levels were examined by immunoblot and RT-PCR, respectively. Gene silencing, binding of Sp1 to DNA and methylation of DNA was performed by siRNA, ChIP assay and sodium bisulfate genomic sequencing, respectively. RESULTS: Sp1-binding sites in the TP promoter were methylated in epidermoid carcinoma. 5-Aza-CdR demethylated Sp1-binding sites and enhanced sensitivity to 5-FU. CONCLUSION: Demethylation of Sp1-binding sites by 5-Aza-CdR was a key factor enhancing 5-FU sensitivity, which may enable more effective treatments for cancer patients with the combination of 5-Aza-CdR and 5-FU.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Metilação de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição Sp1/genética , Timidina Fosforilase/genética , Sítios de Ligação/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Decitabina/metabolismo , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/genética , Timidina Fosforilase/química
15.
Nature ; 571(7766): 489-499, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31341302

RESUMO

Epigenetic research has accelerated rapidly in the twenty-first century, generating justified excitement and hope, but also a degree of hype. Here we review how the field has evolved over the last few decades and reflect on some of the recent advances that are changing our understanding of biology. We discuss the interplay between epigenetics and DNA sequence variation as well as the implications of epigenetics for cellular memory and plasticity. We consider the effects of the environment and both intergenerational and transgenerational epigenetic inheritance on biology, disease and evolution. Finally, we present some new frontiers in epigenetics with implications for human health.


Assuntos
Doença/genética , Epigênese Genética/genética , Epigenômica/tendências , Interação Gene-Ambiente , Envelhecimento/genética , Animais , Cromatina/genética , Cromatina/metabolismo , Metilação de DNA/genética , Variação Genética/genética , Humanos , Neoplasias/genética
16.
Hypertension ; 74(3): 581-589, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31327269

RESUMO

Demethylation of the forkhead box P3 (FOXP3) corresponds with stability of FOXP3 expression and immunosuppressive function of regulatory T cells (Tregs). Previous studies have demonstrated that reduction in Tregs is associated with acute coronary syndrome (ACS). The aim of this study was to establish the relationship between methylation level of FOXP3-TSDR (Treg-specific demethylated region) and clinical outcomes of ACS. We first evaluated the prognostic significance of methylation levels of FOXP3-TSDR in patients with ACS (n=171). Then, we explored the possible mechanism of methylation levels of FOXP3-TSDR on clinical outcomes of ACS in vivo. We analyzed methylation of FOXP3-TSDR, percentage of Tregs in total peripheral blood, and atherosclerotic lesions in aortic root in ApoE-/- mice (n=48; 6 groups). During the follow-up of 4.5±0.8 years, survival free of major adverse cardiovascular events was the lowest in the highest tertile of FOXP3-TSDR methylation (log-rank P=0.004). Multivariate analysis showed that FOXP3-TSDR methylation was independently and positively related to major adverse cardiovascular events (adjusted hazard ratio, 2.13; 95% CI, 1.21-3.75; P=0.009). We observed a duration-dependent increase in the methylation levels of FOXP3-TSDR in mice fed with Western diet at a period of 0, 3, 6, 9, 12, and 15 weeks. Elevated methylation levels of FOXP3-TSDR were significantly correlated of severity of atherosclerosis. We further found that FOXP3-TSDR methylation was inversely related to the percentages of Treg TGF-ß (transforming growth factor-ß) and IL (interleukin)-10 levels. Our results indicate that elevated methylation levels of FOXP3-TSDR are associated with increased risk for adverse outcomes in patients with ACS.


Assuntos
Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/mortalidade , Causas de Morte , Metilação de DNA/genética , Fatores de Transcrição Forkhead/genética , Síndrome Coronariana Aguda/patologia , Adulto , Idoso , Biópsia por Agulha , Estudos de Coortes , Citocinas/metabolismo , Desmetilação , Citometria de Fluxo , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Reação em Cadeia da Polimerase/métodos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Linfócitos T Reguladores/metabolismo
17.
Nat Commun ; 10(1): 2950, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270318

RESUMO

X-chromosome inactivation triggers fusion of A/B compartments to inactive X (Xi)-specific structures known as S1 and S2 compartments. SMCHD1 then merges S1/S2s to form the Xi super-structure. Here, we ask how S1/S2 compartments form and reveal that Xist RNA drives their formation via recruitment of Polycomb repressive complex 1 (PRC1). Ablating Smchd1 in post-XCI cells unveils S1/S2 structures. Loss of SMCHD1 leads to trapping Xist in the S1 compartment, impairing RNA spreading into S2. On the other hand, depleting Xist, PRC1, or HNRNPK precludes re-emergence of S1/S2 structures, and loss of S1/S2 compartments paradoxically strengthens the partition between Xi megadomains. Finally, Xi-reactivation in post-XCI cells can be enhanced by depleting both SMCHD1 and DNA methylation. We conclude that Xist, PRC1, and SMCHD1 collaborate in an obligatory, sequential manner to partition, fuse, and direct self-association of Xi compartments required for proper spreading of Xist RNA.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Cromossomos de Mamíferos/genética , Complexo Repressor Polycomb 1/metabolismo , RNA Longo não Codificante/metabolismo , Cromossomo X/química , Cromossomo X/genética , Animais , Metilação de DNA/genética , Histonas/metabolismo , Lisina/metabolismo , Camundongos , Modelos Genéticos , Inativação do Cromossomo X/genética
18.
Environ Sci Pollut Res Int ; 26(25): 26090-26101, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280440

RESUMO

Global DNA methylation, as an epigenetic modifications, can be a promising genomic marker for monitoring the contaminants and predicting their adverse health effects. The study aims to assess the effects of 16 PAH concentration on the altered DNA methylation levels in the kidney and liver of rock pigeon (Columba livia), as a sentinel species, from Tehran megacity as well as 40 days benzo(a)pyrene in vitro exposure: (0.1, 2.5, 5, 7.5, and 10 mg kg-1 bw). Data indicated that the total LMW-PAH (low molecular weight PAHs) group (120.22, 121.34, 103.69, and 128.79 ng g-1 dw in liver, kidney, skin, and muscle, respectively) in the Tehran samples have higher levels than the other PAHs groups. In addition, the DNA methylation level had negative relation with the total amount of PAHs in liver and kidney. A comparatively higher global DNA hypomethylation (by 8.65% in liver and 3.76% in kidney) was observed in birds exposed to B(a)P. Our results lead us to suggest that DNA hypomethylation in liver and kidney associated with the B(a)P may be useful biomarker discovery (more than the amount of PAH concentration in different tissues of C. livia) in urban areas. In conclusion, based on the overall results assessed, DNA methylation changes in pigeon may show a new target pathway for evaluation of environmental health.


Assuntos
Benzo(a)pireno/química , Metilação de DNA/genética , Hidrocarbonetos Policíclicos Aromáticos/análise , Animais , Columbidae , Monitoramento Ambiental , Irã (Geográfico) , Hidrocarbonetos Policíclicos Aromáticos/química , Espécies Sentinelas
19.
Nat Immunol ; 20(8): 1071-1082, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263277

RESUMO

Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naive cells. Although these cells express distinct markers, their epigenetic architecture and how it contributes to SLE remain poorly understood. To address this, we determined the DNA methylomes, chromatin accessibility profiles and transcriptomes from five human B cell subsets, including a newly defined effector B cell subset, from subjects with SLE and healthy controls. Our data define a differentiation hierarchy for the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Importantly, an SLE molecular signature was already established in resting naive cells and was dominated by enrichment of accessible chromatin in motifs for AP-1 and EGR transcription factors. Together, these factors acted in synergy with T-BET to shape the epigenome of expanded SLE effector B cell subsets. Thus, our data define the molecular foundation of pathogenic B cell dysfunction in SLE.


Assuntos
Subpopulações de Linfócitos B/patologia , Metilação de DNA/genética , Epigênese Genética/genética , Lúpus Eritematoso Sistêmico/genética , Subpopulações de Linfócitos B/imunologia , Montagem e Desmontagem da Cromatina/fisiologia , Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Fator de Transcrição AP-1/genética , Transcriptoma/genética
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