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1.
Zhonghua Zhong Liu Za Zhi ; 42(8): 644-647, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867455

RESUMO

Objective: To explore the application value of lung cancer-related gene methylation in lung cancer diagnosis. Methods: Sixty patients with lung cancer underwent surgery were selected as the case group, and 65 patients with benign lung lesions treated in the same period were recruited as the control group. The methylation levels of lung cancer-related genes including dying-associated protein kinase (DAPK), O-6-methylguanine-DNA methyltransferase (MGMT), APC gene promoter 1A (APC1A) and epithelial mucoprotein gene (ECAD) in the blood samples of two groups of patients were analyzed by methylated PCR-specific method. The relationship between methylation of lung cancer-related genes and lung cancer was analyzed and its diagnostic value in lung cancer was evaluated. Results: The methylation detection rates of DAPK, MGMT, APC1A and ECAD in the case group were 68.3%, 68.3%, 63.3% and 65.0%, respectively, all higher than those of the control group (all P<0.05). The multivariate Logistic regression analysis showed that DAPK (OR=0.709), MGMT (OR=0.793), APC1A (OR=0.163), and ECAD (OR=2.047) were all independent influencing factors for lung cancer (all P<0.05). Analysis of the receiver operating characteristic curve showed that, the area under the curve (AUC) of DAPK, MGMT, APC1A and ECAD methylation test for lung cancer predicting were 0.623, 0.680, 0.620 and 0.648, respectively, while the AUC of the combined four gene methylation for lung cancer predicting was 0.829, higher than the AUC of each gene (all P<0.05). Conclusion: The combined methylation detection of multiple lung cancer related genes can improve the diagnostic value of lung cancer, contribute to the early diagnosis of lung cancer, and have potentially clinical application value.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Proteínas Quinases Associadas com Morte Celular/genética , Neoplasias Pulmonares/diagnóstico , O(6)-Metilguanina-DNA Metiltransferase/genética , Regiões Promotoras Genéticas/genética , Estudos de Casos e Controles , Detecção Precoce de Câncer , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Genética
2.
Ecotoxicol Environ Saf ; 203: 111031, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888610

RESUMO

Bone mineral density (BMD) changes were reported to be associated with excessive fluoride exposure and abnormal expression of RUNX2. However, whether the alteration of methylation status, a most commonly used marker for the alteration of gene expression in epidemiological investigation, of RUNX2 is associated with low-to-moderate fluoride exposure and BMD changes has not been reported. Our study aims to explore the role of RUNX2 promoter methylation in BMD changes induced by low-to-moderate fluoride exposure. A total of 1124 adults (413 men and 711 women) were recruited from Kaifeng City in 2017. We measured BMD using ultrasound bone densitometer. Concentrations of urinary fluoride (UF) were measured using ion-selective electrode, and the participants were grouped into control group (CG) and excessive fluoride group (EFG) according to the concentration of UF. We extracted DNA from fasting peripheral blood samples and then detected the promoter methylation levels of RUNX2 using quantitative methylation-specific PCR. Relationships between UF concentration, RUNX2 promoter methylation and BMD changes were analyzed using generalized linear model and logistic regression. Results showed in EFG (UF concentration > 1.6 mg/L), BMD was negatively correlated with UF concentration (ß: -0.14; 95%CI: -0.26, -0.01) and RUNX2 promoter methylation (ß: -0.13; 95%CI: -0.22, -0.03) in women. The methylation rate of RUNX2 promoter increased by 2.16% for each 1 mg/L increment in UF concentration of women in EFG (95%CI: 0.37, 3.96). No any significant associations between UF concentration, RUNX2 promoter methylation, and BMD were observed in the individuals in CG. Mediation analysis showed that RUNX2 promoter methylation mediated 18.2% (95% CI: 4.2%, 53.2%) of the association between UF concentration and BMD of women in EFG. In conclusion, excessive fluoride exposure (>1.6 mg/L) is associated with changes of BMD in women, and this association is mediated by RUNX2 promoter methylation.


Assuntos
Densidade Óssea/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Exposição Ambiental/análise , Fluoretos/toxicidade , Poluentes Químicos da Água/toxicidade , Absorciometria de Fóton , Adulto , Idoso , Densidade Óssea/genética , China , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Estudos Transversais , Metilação de DNA/efeitos dos fármacos , Feminino , Fluoretos/urina , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Inquéritos e Questionários , Poluentes Químicos da Água/urina
3.
Anticancer Res ; 40(10): 5659-5666, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988890

RESUMO

BACKGROUND/AIM: Long interspersed nuclear element-1 (LINE-1) methylation status is a marker for global DNA methylation. However, the relationship between LINE-1 methylation and the biology of lung adenocarcinoma remains unclear. Here, we aimed to examine the role of LINE-1 in lung cancer. MATERIALS AND METHODS: LINE-1 methylation levels were quantified by bisulfite pyrosequencing of resected tumor specimens from 162 patients with lung adenocarcinoma. The relationships of LINE-1 methylation with clinicopathological factors, gene mutations, and Ki-67 immunoreactivity were investigated. RESULTS: LINE-1 hypomethylation was associated with tumor invasion and advanced stage. TP53 mutations were more frequently detected in the LINE-1 hypomethylation group than in the hypermethylation group. LINE-1 hypomethylation was associated with poor recurrence-free survival, high maximum standardized uptake value in positron-emission tomography, and high Ki-67 expression in tumors. CONCLUSION: LINE-1 hypomethylation was associated with high-grade malignancy and poor prognosis in lung adenocarcinoma, but was not related to driver mutations.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Metilação de DNA/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Núcleo Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Antígeno Ki-67/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Proteína Supressora de Tumor p53/genética
4.
DNA Cell Biol ; 39(10): 1838-1849, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32876480

RESUMO

The breast cancer gene 1 (BRCA1) is a tumor suppressor, and mutations or epigenetic inactivation will increase the risk of breast cancer oncogenesis. The current research aimed to explore the relationship between BRCA1 expression, prognosis, and tumor immunity in hepatocellular carcinoma (HCC). In this study, BRCA1 expression was analyzed via multiple online databases and its association with clinical characteristics, prognosis and genetic alterations was identified using the original The Cancer Genome Atlas-liver hepatocellular carcinoma cohorts. DNA methylation sites and their prognostic values were analyzed using MethSurv. The correlations between BRCA1 and immune infiltration were investigated via Tumor Immune Estimation Resource. As results, BRCA1 was significantly upregulated in tumor tissues in multiple HCC cohorts. Besides, high BRCA1 expression was correlated with race, advanced T stage, clinical stage, poor tumor grade, MSI status, and worse prognosis. Notably, BRCA1 expression was positively correlated with infiltration levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. The current findings imply that BRCA1 is associated with prognosis and immune infiltration, laying foundations for in-depth research on the role of BRCA1 in HCC.


Assuntos
Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteína BRCA1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Movimento Celular , Metilação de DNA , Células Dendríticas/imunologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Linfócitos/imunologia , Macrófagos/imunologia
5.
Commun Biol ; 3(1): 538, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994472

RESUMO

The advent of portable nanopore sequencing devices has enabled DNA and RNA sequencing to be performed in the field or the clinic. However, advances in in situ genomics require parallel development of portable, offline solutions for the computational analysis of sequencing data. Here we introduce Genopo, a mobile toolkit for nanopore sequencing analysis. Genopo compacts popular bioinformatics tools to an Android application, enabling fully portable computation. To demonstrate its utility for in situ genome analysis, we use Genopo to determine the complete genome sequence of the human coronavirus SARS-CoV-2 in nine patient isolates sequenced on a nanopore device, with Genopo executing this workflow in less than 30 min per sample on a range of popular smartphones. We further show how Genopo can be used to profile DNA methylation in a human genome sample, illustrating a flexible, efficient architecture that is suitable to run many popular bioinformatics tools and accommodate small or large genomes. As the first ever smartphone application for nanopore sequencing analysis, Genopo enables the genomics community to harness this cheap, ubiquitous computational resource.


Assuntos
Betacoronavirus/genética , Biologia Computacional/métodos , Genoma Humano , Genoma Viral , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento Completo do Genoma/métodos , Betacoronavirus/patogenicidade , Telefone Celular/instrumentação , Biologia Computacional/instrumentação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Metilação de DNA , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Nanoporos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Sequenciamento Completo do Genoma/instrumentação
6.
PLoS Med ; 17(9): e1003263, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941469

RESUMO

BACKGROUND: Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population. METHODS AND FINDINGS: This was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1-methylation testing. Women <50 years, with strong family histories and/or indicative tumour molecular features, underwent MMR germline sequencing. Somatic MMR sequencing was performed when indicative molecular features were unexplained by LS or MLH1-hypermethylation. The main outcome measures were the prevalence of LS in an unselected EC population and the diagnostic accuracy of clinical and tumour testing strategies for risk stratifying women with EC for MMR germline sequencing. In total, 500 women participated in the study; only 2 (<1%) declined. Germline sequencing was indicated and conducted for 136 and 135 women, respectively. A total of 16/500 women (3.2%, 95% CI 1.8% to 5.1%) had LS, and 11 more (2.2%) had MMR variants of uncertain significance. Restricting testing to age <50 years, indicative family history (revised Bethesda guidelines or Amsterdam II criteria) or endometrioid histology alone would have missed 9/16 (56%), 8/13 (62%) or 9/13 (69%), and 5/16 (31%) cases of LS, respectively. In total 132/500 tumours were MMR deficient by IHC of which 83/132 (63%) had MLH1-hypermethylation, and 16/49 (33%) of the remaining patients had LS (16/132 with MMR deficiency, 12%). MMR-IHC with targeted MLH1-methylation testing was more discriminatory for LS than MSI with targeted methylation testing, with 100% versus 56.3% (16/16 versus 9/16) sensitivity (p = 0.016) and equal 97.5% (468/484) specificity; 64% MSI-H and 73% MMR deficient tumours unexplained by LS or MLH1-hypermethylation had somatic MMR mutations. The main limitation of the study was failure to conduct MMR germline sequencing for the whole study population, which means that the sensitivity and specificity of tumour triage strategies for LS detection may be overestimated, although the risk of LS in women with no clinical or tumour predictors is expected to be extremely low. CONCLUSIONS: In this study, we observed that age, family history, and histology are imprecise clinical correlates of LS-EC. IHC outperformed MSI for tumour triage and reliably identified both germline and somatic MMR mutations. The 3.2% proportion of LS-EC is similar to colorectal cancer, supporting unselected screening of EC for LS.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer/métodos , Neoplasias do Endométrio/genética , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Estudos Transversais , Metilação de DNA/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/diagnóstico , Feminino , Testes Genéticos/métodos , Humanos , Imuno-Histoquímica , Programas de Rastreamento/métodos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Reino Unido
7.
Nat Commun ; 11(1): 4873, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978376

RESUMO

Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous neurodevelopmental disorder. Despite this heterogeneity, previous studies have shown patterns of molecular convergence in post-mortem brain tissue from autistic subjects. Here, we integrate genome-wide measures of mRNA expression, miRNA expression, DNA methylation, and histone acetylation from ASD and control brains to identify a convergent molecular subtype of ASD with shared dysregulation across both the epigenome and transcriptome. Focusing on this convergent subtype, we substantially expand the repertoire of differentially expressed genes in ASD and identify a component of upregulated immune processes that are associated with hypomethylation. We utilize eQTL and chromosome conformation datasets to link differentially acetylated regions with their cognate genes and identify an enrichment of ASD genetic risk variants in hyperacetylated noncoding regulatory regions linked to neuronal genes. These findings help elucidate how diverse genetic risk factors converge onto specific molecular processes in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Epigenômica/métodos , RNA Mensageiro/metabolismo , Transcriptoma , Encéfalo/metabolismo , Metilação de DNA , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genômica , Histonas/metabolismo , Humanos , MicroRNAs
8.
Nat Commun ; 11(1): 4858, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978382

RESUMO

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.


Assuntos
Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores Tumorais , Quimioterapia Adjuvante , Cisplatino/uso terapêutico , Metilação de DNA , Tratamento Farmacológico , Instabilidade Genômica , Humanos , Mutação , Terapia Neoadjuvante , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transcriptoma , Neoplasias da Bexiga Urinária/patologia
9.
Medicine (Baltimore) ; 99(39): e22389, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991460

RESUMO

To investigate the molecular mechanisms of later metabolic health changes in large for gestational age (LGA) newborns by analyzing deoxyribonucleic acid (DNA) methylation patterns in the placenta of LGA and appropriate for gestational age (AGA) newborns.A total of 6 placentas of LGA and 6 placentas of AGA newborns were enrolled as LGA group and AGA group. DNA methylation was analyzed using the Illumina Infinium Human MethylationEPIC BeadChip microarrays and verified via pyrosequencing and reverse transcription-quantitative real-time polymerase chain reaction. Functional enrichment analysis were constructed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis based on the differentially methylated regions between LGA and AGA groups.Clinical investigation showed that LGA newborns had significantly lower hemoglobin and blood glucose compared to AGA newborns. Birth weight was negatively correlated to hemoglobin and blood glucose. Genome-wide DNA methylation analysis identified 17 244 methylation variable positions achieving genome-wide significance (adjusted P < .05). 34% methylation variable positions were located in the gene promoter region. A total of 117 differentially methylated regions were revealed by bump hunting analysis, which mapped to 107 genes. Function analysis showed 13 genes enriched in "adhesion and infection process, endocrine and other factor-regulated calcium reabsorption, calcium signaling pathway and transmembrane transport". Four genes linked to type II diabetes mellitus. Among the 13 genes, we selected GNAS and calcium voltage-gated channel subunit alpha1 G for independent verification of pyrosequencing, and the messenger ribonucleic acid levels of guanine nucleotide binding protein, calcium voltage-gated channel subunit alpha1 G, DECR1, and FK506 binding protein 11 were verified by reverse transcription-quantitative real-time polymerase chain reaction.DNA methylation variation and gene expression differences in placental samples were associated with LGA newborns, which linking the effect of intrauterine environment to regulation of the offspring's gene expression. Furthermore, pathway analysis suggested that intrauterine environment affecting fetal growth might had a functional impact on multiple signaling pathways involved in fetal growth, metabolism, and inflammation. Further studies were required to understand the differences of methylation patterns.


Assuntos
Metilação de DNA , Epigênese Genética , Desenvolvimento Fetal , Síndrome Metabólica/etiologia , Placenta/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Adulto Jovem
10.
Adv Exp Med Biol ; 1255: 1-6, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949386

RESUMO

Clinical single-cell biomedicine has become a new emerging discipline, which integrates single-cell RNA and DNA sequencing, proteomics, and functions with clinical phenomes, therapeutic responses, and prognosis. It is of great value to discover disease-, phenome-, and therapy-specific diagnostic biomarkers and therapeutic targets on the basis of the principle of clinical single-cell biomedicine. This book reviews the roles of single-cell sequencing and methylation in diseases and explores disease-specific alterations of single-cell sequencing and methylation, especially focusing on potential applications of methodologies on human single-cell sequencing and methylation, on potential correlations between those changes with pulmonary diseases, and on potential roles of signaling pathways that cause heterogeneous cellular responses during treatment. This book also emphasizes the importance of methodologies in clinical practice and application, the potential of perspectives, challenges and solutions, and the significance of single-cell preparation standardization. Alterations of DNA and RNA methylation, demethylation in lung diseases, and a deep knowledge about the regulation and function of target gene methylation for diagnosing and treating diseases at the early stage are also provided. Importantly, this book aims to apply the measurement of single-cell sequencing and methylation for clinical diagnosis and treatment and to understand clinical values of those parameters and to headline and foresee the potential values of the application of single-cell sequencing in non-cancer diseases.


Assuntos
Metilação de DNA , Doença/genética , Análise de Sequência , Análise de Célula Única , DNA/genética , DNA/metabolismo , Humanos , Proteômica , RNA/genética , RNA/metabolismo
11.
Adv Exp Med Biol ; 1255: 51-62, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949389

RESUMO

DNA methylations, including global methylation pattern and specific gene methylation, are associated with pathogenesis and progress of pulmonary fibrosis. This chapter illustrates alteration of DNA methylation in pulmonary fibrosis as a predictive or prognostic factor. Treatment with the DNA methylation inhibitors will be an emerging anti-fibrosis therapy, although we are still in the pre-clinical stage of using epigenetic markers as potential targets for biomarkers and therapeutic interventions.


Assuntos
Metilação de DNA , Fibrose Pulmonar/genética , Epigenômica , Humanos
12.
Adv Exp Med Biol ; 1255: 63-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949390

RESUMO

This chapter overviews roles of DNA methylation in inflammatory cell biology with the focuses on lymphocytes and macrophages/monocytes in lung diseases, although the molecular mechanisms by which target genes are methylated and regulated in lung diseases remain unclear. Most of epigenetic studies on DNA methylation of target genes in lung diseases mainly demonstrated the correlation of DNA methylation of target genes with the levels of other corresponding factors, with the specificity of clinical phenomes, and with the severity of lung diseases. There is an urgent need to identify and validate the specificity and regulatory mechanisms of inflammatory cell epigenetics in depth. The epigenetic heterogeneity among different subsets of T cells and among promoters or non-promoters of target genes should be furthermore clarified in acute or chronic lung diseases and cancers. The hyper/hypo-methylation and modifications of chromosol and extrachromosomal DNA may result in alternations in proteins within inflammatory cells, which can be identified as disease-specific biomarkers and therapeutic targets.


Assuntos
Metilação de DNA , Inflamação/genética , Pneumopatias/genética , Pneumopatias/patologia , Epigênese Genética , Epigenômica , Humanos
13.
Adv Exp Med Biol ; 1255: 73-81, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949391

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic complex lung disease with no specific treatment and poor prognosis, characterized by the pulmonary progressive fibrosis and dysfunctions that lead to respiratory failure. Several factors may impact the progress of IPF, including age, cigarette smoking, and dusts, of which genetic and epigenetic factors mainly contribute to lung tissue fibrosis. DNA methylation is one of epigenetic processes that occur in many diseases and regulate chromosomal and extrachromosomal DNA functions in response to environmental exposures. The methylation plays pivotal roles in regulation of gene expression to facilitate the formation of fibroblastic foci and lung fibrosis. This chapter will describe alterations and effects of the DNA methylation on gene expression, the potential application of DNA methylation as a biomarker, and significance as therapeutic targets. Those understanding will provide us new insight into the treatment and prognosis of IPF.


Assuntos
Metilação de DNA , Fibrose Pulmonar Idiopática/genética , Epigênese Genética , Epigenômica , Expressão Gênica , Humanos
14.
Adv Exp Med Biol ; 1255: 83-98, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949392

RESUMO

Chronic obstructive pulmonary disease (COPD) is a lung disease affected by both genetic and environmental factors. Therefore, the role of epigenetics in the pathogenesis of COPD has attracted much attention. As one of the three epigenetic mechanisms, DNA methylation has been extensively studied in COPD. The present review aims at overviewing the effect of DNA methylation on etiology, pathogenesis, pathophysiological changes, and complications of COPD. The clarification of aberrant methylation of target genes, which play important roles in the initiation and progression of COPD, will provide new disease-specific biomarker and targets for early diagnosis and therapy.


Assuntos
Metilação de DNA , Doença Pulmonar Obstrutiva Crônica/genética , Epigênese Genética , Epigenômica , Humanos
15.
Adv Exp Med Biol ; 1255: 99-108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949393

RESUMO

Lung carcinoma is the most frequently diagnosed malignant neoplasms and mainly consists of small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). Large number of lung carcinoma patients have poor outcomes due to the late diagnosis and the limited therapeutic options. Previous attempts have proved that the evolution of lung carcinoma is a multistep molecular aberration which various genetic or epigenetic alterations may be take part in. Among these molecular aberrations, the inactivation of tumor suppressor gene has been widely observed in all types of carcinoma including lung carcinoma. As a vital inactivated mechanism, DNA methylation of tumor suppressor gene is frequently found in lung cancer. To gain exhaustive comprehension of the carcinogenesis of lung carcinoma, we summarize our current knowledge on DNA methylation of RASSF1 (RAS-Association Domain Family 1) and its clinical significance in lung carcinoma.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Neoplasias Pulmonares/genética , Proteínas Supressoras de Tumor/genética , Genes Supressores de Tumor , Humanos
16.
Adv Exp Med Biol ; 1255: 123-132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949395

RESUMO

Hypermethylation can downregulate many tumor suppressor gene expressions. Aplasia Ras homologue member I (ARHI, DIRAS3) is one of the maternally imprinted tumor suppressors in the RAS superfamily. This chapter overviewed the importance of ARHI methylation and expression phenomes in various types of cancers, although the exact mechanisms remain unclear. As an imprinted gene, aberrant DNA methylation of the paternal allele of ARHI was identified as a primary inhibitor of ARHI expression. The role of methylation in the CpG islands of the ARHI promoter region vary among ovarian cancers, breast cancers, hepatocellular carcinoma, colon cancers, pancreatic cancer osteosarcoma, glial tumors, follicular thyroid carcinoma, or lung cancers. The methylation of ARHI provides a new insight to understand molecular mechanisms of tumorigenesis and progression of cancers.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Neoplasias/genética , Regiões Promotoras Genéticas , Proteínas rho de Ligação ao GTP/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Humanos
17.
Adv Exp Med Biol ; 1255: 133-142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949396

RESUMO

Lung cancer is the leading cause of death from cancer in China. The lack of early screening technologies makes most patients to be diagnosed at advanced stages with a poor prognosis which often miss the best treatment opportunities. Thus, identifying biomarkers for minimally invasive detection and prognosis of early stage disease is urgently needed. Genetic and epigenetic alterations that promote tumorigenesis and metastasis exist in multiple cancers. These aberrant alterations usually represent early events in cancer progression suggesting their potential applications as a biomarker for cancer prediction. Studies have shown that DNA methylation is one of the key factors in progression of lung cancer. P16 promoter methylation is one of the most common epigenetic change plays a key role in lung cancer. In this review, we highlight the p16 gene methylation and its clinical significance in lung cancer.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Genes p16 , Neoplasias Pulmonares/genética , Humanos , Regiões Promotoras Genéticas
18.
Nat Commun ; 11(1): 4642, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934200

RESUMO

Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis. Lost expression of a key DNA demethylation enzyme TET2 is associated with human cancers and has been linked to stem cell traits in vitro; however, whether and how TET2 regulates mammary stem cell fate and mammary tumorigenesis in vivo remains to be determined. Here, using our recently established mammary specific Tet2 deletion mouse model, the data reveals that TET2 plays a pivotal role in mammary gland development and luminal lineage commitment. We show that TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1, three key genes that are known to coordinately orchestrate mammary luminal lineage specification and endocrine response, and also are often silenced by DNA methylation in aggressive breast cancers. Furthermore, Tet2 deletion-PyMT breast cancer mouse model exhibits enhanced mammary tumor development with deficient ERα expression that confers tamoxifen resistance in vivo. As a result, this study elucidates a role for TET2 in governing luminal cell differentiation and endocrine response that underlies breast cancer resistance to anti-estrogen treatments.


Assuntos
Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Estradiol/metabolismo , Estrogênios/metabolismo , Glândulas Mamárias Animais/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem da Célula , Metilação de DNA , Proteínas de Ligação a DNA/genética , Sistema Endócrino/metabolismo , Epigênese Genética , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Glândulas Mamárias Animais/fisiopatologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética
19.
Nat Commun ; 11(1): 4505, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908148

RESUMO

Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce. Aberrant patterns of DNA methylation in gametes may set the stage for transmission into future generations. Here, we describe a viable hypomorphic allele of dnmt1 in zebrafish that causes widespread demethylation of CpG dinucleotides in sperm and somatic tissues. We find that homozygous mutants are essentially normal, with the exception of drastically impaired lymphopoiesis, affecting both larval and adult phases of T cell development. The phenotype of impaired larval (but not adult) T cell development is transmitted to subsequent generations by genotypically wildtype fish. We further find that about 200 differentially methylated regions in sperm DNA of transmitting and non-transmitting males, including hypermethylated sites associated with runx3 and rptor genes, whose reduced activities are associated with impaired larval T cell development. Our results indicate a particular sensitivity of larval T cell development to transgenerationally inherited epimutations.


Assuntos
Diferenciação Celular/genética , Genes Recessivos , Larva/crescimento & desenvolvimento , Linfopoese/genética , Linfócitos T/fisiologia , Alelos , Animais , Animais Geneticamente Modificados , Subunidade alfa 3 de Fator de Ligação ao Core/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Epigênese Genética , Feminino , Genética , Larva/citologia , Masculino , Mutação , Proteína Regulatória Associada a mTOR/genética , Espermatozoides/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
20.
Nat Commun ; 11(1): 4529, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913184

RESUMO

Although Huntington's disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10-7) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10-26). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10-8) and in the transgenic sheep model (p = 2.4 × 10-88). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10-7) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10-9), GRIK4 (p = 3.0 × 10-8), and COX4I2 (p = 6.5 × 10-8). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.


Assuntos
Metilação de DNA , Epigênese Genética , Proteína Huntingtina/genética , Doença de Huntington/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Animais Geneticamente Modificados , Comportamento Animal , Ilhas de CpG/genética , Estudos Transversais , Modelos Animais de Doenças , Progressão da Doença , Feminino , Seguimentos , Técnicas de Introdução de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Carga Global da Doença , Humanos , Doença de Huntington/sangue , Doença de Huntington/diagnóstico , Doença de Huntington/epidemiologia , Estudos Longitudinais , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Proteínas Recombinantes/genética , Sistema de Registros/estatística & dados numéricos , Índice de Gravidade de Doença , Ovinos , Adulto Jovem
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