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1.
Medicine (Baltimore) ; 98(41): e17468, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593107

RESUMO

INTRODUCTION: Microtia is a congenital malformation of the external and middle ear caused by the abnormal development of the first and second zygomatic arch and the first sulcus. There is currently no consensus concerning the pathogenesis and etiology of microtia; genetic and environmental factors may play a role. Gene-based studies have focused on finding the genes that cause microtia and on gene function defects. However, no clear pathogenic genes have so far been identified. Microtia is multifactorial; gene function defects cannot completely explain its pathogenesis. In recent years, the epigenetic aspects of microtia have begun to receive attention. CONCLUSIONS: Analysis of the existing data suggests that certain key genes and pathways may be the underlying cause of congenital microtia. However, further exploration is needed.


Assuntos
Microtia Congênita/genética , Epigênese Genética/genética , Epigenômica , Humanos
2.
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
3.
Anticancer Res ; 39(10): 5573-5579, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570452

RESUMO

BACKGROUND/AIM: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer, frequently infected with Merkel cell polyomavirus (MCPyV). H3K27me3 acts as a repressive histone modification that epigenetically controls gene transcription. The aim of this study was to examine H3K27me3 expression in MCC. MATERIALS AND METHODS: H3K27me3 expression levels were immunohistochemically analyzed in 20 MCPyV-positive MCCs, 15 MCPyV-negative MCCs with squamous cell carcinoma (SCC) (combined MCCs), and six MCPyV-negative pure MCCs. RESULTS: Reduced H3K27me3 expression was variously observed in MCCs. H3K27me3 H-score was significantly lower in MCPyV-negative MCCs than in MCPyV-positive MCCs (p=0.002). H3K27me3 expression was significantly lower in MCPyV-negative combined MCC component than in MCPyV-positive MCCs (p<0.001), MCPyV-negative pure MCCs (p=0.036), or pure MCC histology (p<0.001). Kaplan-Meier analysis showed no association of H3K27me3 with outcome. CONCLUSION: Differential reduction in H3K27me3 expression was observed based on MCPyV status and morphological type. These results implicate H3K27me3-mediated epigenetic changes in tumorigenesis of MCC, especially in MCPyV-negative MCC combined with SCC.


Assuntos
Carcinoma de Célula de Merkel/genética , Carcinoma de Células Escamosas/genética , Histonas/genética , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinoma de Célula de Merkel/virologia , Carcinoma de Células Escamosas/virologia , Epigênese Genética/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Poliomavírus das Células de Merkel/patogenicidade , Pessoa de Meia-Idade , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/virologia , Neoplasias Cutâneas/virologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/virologia
6.
Georgian Med News ; (290): 124-127, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31322528

RESUMO

Autism spectrum disorders (ASD) are considered an epidemic - only in the last 5 years the incidence of pathology has increased from 1: 166 to 1:68 children. The main role in the pathogenesis of ASD currently belongs to the violation of the epigenetic status in the form of gene polymorphisms. An example is the polymorphic variants of the genes of the folate-methionine cycle enzymes, which regulate the epigenetic status through a methylation process. The article presents a case of autism spectrum disorder against the background of impaired epigenetic status (metabolic dopamine neurotransmitters and the methylation cycle). Individually selected metabolic correction based on biochemical parameters allowed improving behavior, stimulating speech development, stopping long subfebrile and hypersalivation.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/reabilitação , Epigênese Genética/genética , Ferredoxina-NADP Redutase/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Transtorno Autístico , Criança , Metilação de DNA , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Receptores de Dopamina D2
7.
Int Arch Allergy Immunol ; 180(2): 120-127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256157

RESUMO

BACKGROUND: Allergen immunotherapy (AIT) is the only etiological and potentially curative therapy for allergic rhinitis (AR). OBJECTIVES: We sought to investigate the role of epigenetic regulator enhancer of zeste homolog 2 (EZH2) in the activation of dendritic cells (DCs) in AIT. METHOD: In this study, EZH2 expression in circulating myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) were evaluated using flow cytometry. Clinical information from 56 AR patients receiving AIT was collected, including 30 subjects with subcutaneous immunotherapy (SCIT) and 26 subjects with sublingual immunotherapy (SLIT). In vitro, the effect of EZH2 inhibitor, 3 Deazaneplanocin A (DZNep), on the phenotypic and functional activation of monocyte-derived DCs (moDCs) was evaluated. RESULTS: EZH2 expression in circulating mDCs and pDCs were both negatively correlated to treatment time of AIT (r = -0.39, p = 0.003 and r = -0.47, p = 0.0002, respectively). Furthermore, there was a higher correlation between EZH2 expression and AIT treatment time in the SCIT group compared to that of the SLIT group in mDCs (r = -0.42, p = 0.02 vs. r = -0.23, p = 0.26)and pDCs (r = -0.52, p = 0.003 vs. r = -0.33, p = 0.10). In vitro, the co-stimulatory molecules on moDCs, such as CD80, CD86, and CD83, were significantly inhibited by DZNep in a dose-dependent manner. The -DC-driven T-cell proliferation was suppressed by DZNep (MD = 22.88, 95% CI 7.809-37.96, p < 0.05). CONCLUSIONS: Our study shows that EZH2, which is required in the activation of DCs, mediates the epigenetic modification in AIT and stresses the importance of patient adherence during AIT.


Assuntos
Adenosina/análogos & derivados , Células Dendríticas/imunologia , Dessensibilização Imunológica/métodos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Rinite Alérgica/imunologia , Adenosina/uso terapêutico , Adulto , Proliferação de Células/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Epigênese Genética/genética , Epigênese Genética/imunologia , Feminino , Humanos , Interleucina-10/análise , Interleucina-6/análise , Masculino , Cooperação do Paciente , Rinite Alérgica/patologia , Adulto Jovem
8.
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
9.
Nurs Outlook ; 67(4): 337-344, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31248628

RESUMO

BACKGROUND: A rapidly expanding literature suggests that individuals of the same chronological age show significant variation in biological age. PURPOSE: The purpose of this article is to review the literature surrounding epigenetic age as estimated by DNA methylation, involving the addition or removal of methyl groups to DNA that can alter gene expression without changing the DNA sequence. METHODS: This state of the science literature review summarizes current approaches in epigenetic age determination and applications of aging algorithms. FINDINGS: A number of algorithms estimate epigenetic age using DNA methylation markers, primarily among adults. Algorithm application has focused on determining predictive value for risk of disease and death and identifying antecedents to age acceleration. Several studies have incorporated epigenetic age to evaluate intervention effectiveness. DISCUSSION: As the research community continues to refine aging algorithms, there may be opportunity to promote health from a precision health perspective.


Assuntos
Envelhecimento/genética , Envelhecimento/fisiologia , Metilação de DNA/fisiologia , Epigênese Genética/genética , Marcadores Genéticos/fisiologia , Promoção da Saúde/métodos , Medicina de Precisão/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
PLoS Genet ; 15(6): e1008181, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31216276

RESUMO

The increasing worldwide prevalence of Hepatocellular carcinoma (HCC), characterized by resistance to conventional chemotherapy, poor prognosis and eventually mortality, place it as a prime target for new modes of prevention and treatment. Hepatitis C Virus (HCV) is the predominant risk factor for HCC in the US and Europe. Multiple epidemiological studies showed that sustained virological responses (SVR) following treatment with the powerful direct acting antivirals (DAAs), which have replaced interferon-based regimes, do not eliminate tumor development. We aimed to identify an HCV-specific pathogenic mechanism that persists post SVR following DAAs treatment. We demonstrate that HCV infection induces genome-wide epigenetic changes by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) for histone post-translational modifications that are epigenetic markers for active and repressed chromatin. The changes in histone modifications correlate with reprogramed host gene expression and alter signaling pathways known to be associated with HCV life cycle and HCC. These epigenetic alterations require the presence of HCV RNA or/and expression of the viral proteins in the cells. Importantly, the epigenetic changes induced following infection persist as an "epigenetic signature" after virus eradication by DAAs treatment, as detected using in vitro HCV infection models. These observations led to the identification of an 8 gene signature that is associated with HCC development and demonstrate persistent epigenetic alterations in HCV infected and post SVR liver biopsy samples. The epigenetic signature was reverted in vitro by drugs that inhibit epigenetic modifying enzyme and by the EGFR inhibitor, Erlotinib. This epigenetic "scarring" of the genome, persisting following HCV eradication, suggest a novel mechanism for the persistent pathogenesis of HCV after its eradication by DAAs. Our study offers new avenues for prevention of the persistent oncogenic effects of chronic hepatitis infections using specific drugs to revert the epigenetic changes to the genome.


Assuntos
Carcinoma Hepatocelular/genética , Epigênese Genética/genética , Hepacivirus/genética , Hepatite C/genética , Neoplasias Hepáticas/genética , Idoso , Antivirais/administração & dosagem , Biópsia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Cromatina/genética , Epigênese Genética/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepatite C/tratamento farmacológico , Hepatite C/patologia , Hepatite C/virologia , Código das Histonas/genética , Histonas/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Interferons/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Resposta Viral Sustentada
11.
BMC Plant Biol ; 19(1): 282, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248374

RESUMO

BACKGROUND: Heavy metal toxicity has become a major threat to sustainable crop production worldwide. Thus, considerable interest has been placed on deciphering the mechanisms that allow plants to combat heavy metal stress. Strategies to deal with heavy metals are largely focused on detoxification, transport and/or sequestration. The P1B subfamily of the Heavy Metal-transporting P-type ATPases (HMAs) was shown to play a crucial role in the uptake and translocation of heavy metals in plants. Here, we report the locus-specific expression changes in the rice HMA genes together with several low-copy cellular genes and transposable elements upon the heavy metal treatment and monitored the transgenerational inheritance of the altered expression states. We reveal that plants cope with heavy metal stress by making heritable changes in gene expression and further determined gene-specific responses to heavy metal stress. RESULTS: We found most HMA genes were upregulated in response to heavy metal stress, and furthermore found evidence of transgenerational memory via changes in gene regulation even after the removal of heavy metals. To explore whether DNA methylation was also altered in response to the heavy metal stress, we selected a Tos17 retrotransposon for bisulfite sequencing and studied its methylation state across three generations. We found the DNA methylation state of Tos17 was altered in response to the heavy metal stress and showed transgenerational inheritance. CONCLUSIONS: Collectively, the present study elucidates heritable changes in gene expression and DNA methylation in rice upon exposure to heavy metal stress and discusses implications of this knowledge in breeding for heavy metal tolerant crops.


Assuntos
Adenosina Trifosfatases/genética , Epigênese Genética/genética , Expressão Gênica/genética , Metais Pesados/efeitos adversos , Oryza/genética , Proteínas de Plantas/genética , Poluentes do Solo/efeitos adversos , Adenosina Trifosfatases/metabolismo , Oryza/enzimologia , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Estresse Fisiológico
12.
Curr Top Med Chem ; 19(15): 1350-1362, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31215380

RESUMO

Macrophages are essential for supporting tissue homeostasis, regulating immune response, and promoting tumor progression. Due to its heterogeneity, macrophages have different phenotypes and functions in various tissues and diseases. It is becoming clear that epigenetic modification playing an essential role in determining the biological behavior of cells. In particular, changes of DNA methylation, histone methylation and acetylation regulated by the corresponding epigenetic enzymes, can directly control macrophages differentiation and change their functions under different conditions. In addition, epigenetic enzymes also have become anti-tumor targets, such as HDAC, LSD1, DNMT, and so on. In this review, we presented an overview of the latest progress in the study of macrophages phenotype and function regulated by epigenetic modifications, including DNA methylation and histone modifications, to better understand how epigenetic modification controls macrophages phenotype and function in inflammation-associated diseases, and the application prospect in anti-tumor.


Assuntos
Antineoplásicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Acetilação/efeitos dos fármacos , Animais , Antineoplásicos/química , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/genética , Histonas/efeitos dos fármacos , Histonas/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Metilação/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia
13.
Life Sci ; 231: 116576, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31211998

RESUMO

AIMS: Studies suggest that cardiovascular function in offspring can be epigenetically programmed by environmental changes during pregnancy. CaV1.2 channel plays a major role in the regulation of the vascular tone. This study investigated the effects and underlying mechanisms of exercise during pregnancy on CaV1.2 channel functional remodeling in hypertensive offspring. MAIN METHODS: Exercise groups were subjected to swimming at the first day of pregnancy and on a regular schedule thereafter for 3 weeks. Their offspring (6-month-old, male) were tested for baseline blood pressure, cardiovascular response, and vascular tone of the mesenteric artery. Mesenteric artery smooth muscle cells were taken to study the whole-cell current of the CaV1.2 channel. Western blotting, RT-PCR and DNA bisulfite sequencing PCR were performed to study the protein, mRNA expression and DNA methylation of the CaV1.2 channel α1C subunit. KEY FINDINGS: Exercise during pregnancy reduced the pressor response to norepinephrine and Bay K8644, and the depressor response to nifedipine in offspring of hypertensive rats. The level of the CaV1.2 channel in norepinephrine-induced vasoconstrictions decreased, and the whole-cell current of the CaV1.2 channel declined in the SHR-EX group. Further studies found that exercise during pregnancy reduced the protein and mRNA expression of the CaV1.2 channel α1C subunit and upregulated DNA methylation of the Cacna1c gene promoter region in the hypertensive offspring. SIGNIFICANCE: These data suggest that exercise during pregnancy improves vascular functional remodeling in offspring of hypertensive rats, downregulating the CaV1.2 channel function and protein expression, a change that is most likely caused by DNA methylation.


Assuntos
Canais de Cálcio Tipo L/fisiologia , Hipertensão/fisiopatologia , Condicionamento Físico Animal/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Metilação de DNA/efeitos dos fármacos , Regulação para Baixo , Epigênese Genética/genética , Repressão Epigenética , Feminino , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Gravidez , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Regulação para Cima , Vasoconstrição/efeitos dos fármacos
14.
Nat Commun ; 10(1): 2396, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160561

RESUMO

Modern genetic studies indicate that human brain evolution is driven primarily by changes in gene regulation, which requires understanding the biological function of largely non-coding gene regulatory elements, many of which act in tissue specific manner. We leverage chromatin interaction profiles in human fetal and adult cortex to assign three classes of human-evolved elements to putative target genes. We find that human-evolved elements involving DNA sequence changes and those involving epigenetic changes are associated with human-specific gene regulation via effects on different classes of genes representing distinct biological pathways. However, both types of human-evolved elements converge on specific cell types and laminae involved in cerebral cortical expansion. Moreover, human evolved elements interact with neurodevelopmental disease risk genes, and genes with a high level of evolutionary constraint, highlighting a relationship between brain evolution and vulnerability to disorders affecting cognition and behavior. These results provide novel insights into gene regulatory mechanisms driving the evolution of human cognition and mechanisms of vulnerability to neuropsychiatric conditions.


Assuntos
Córtex Cerebral/embriologia , Epigênese Genética/genética , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/genética , Encéfalo/embriologia , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Predisposição Genética para Doença , Humanos , Elementos Reguladores de Transcrição/genética
16.
Cell Biochem Funct ; 37(5): 340-347, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31062382

RESUMO

This study was designed to investigate the molecular mechanism and biological roles of long non-coding RNA (lncRNA) brain-derived neurotrophic factor antisense (BDNF-AS) in colorectal cancer (CRC). The quantitative real-time PCR (qRT-PCR) and western blotting were performed to detect the expressions of lncRNA BDNF-AS and glycogen synthase kinase-3ß (GSK-3ß) in human CRC tissues and cell lines. The cell proliferation, transwell migration, and invasion assays were carried out to evaluate the effect of lncRNA BDNF-AS on the growth of CRC cells. RNA pull-down and RNA immunoprecipitation (RIP) assays were conducted to confirm the interaction between lncRNA BDNF-AS and enhancer of Zeste Homologue 2 (EZH2). Chromatin immunoprecipitation (ChIP) assay was used to verify the enrichment of EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) in the promoter region of GSK-3ß in CRC cells. LncRNA BDNF-AS expression was significantly decreased, while GSK-3ß was highly expressed in human CRC tissues and cell lines. Moreover, lncRNA BDNF-AS induced inhibition of proliferation, migration, and invasion of CRC cells via inhibiting GSK-3ß expression. Mechanistically, BDNF-AS led to GSK-3ß promoter silencing in CRC cells through recruitment of EZH2. In conclusion, lncRNA BDNF-AS functioned as an oncogene in CRC and shed new light on lncRNA-directed therapeutics in CRC. SIGNIFICANCE OF THE STUDY: LncRNA BDNF-AS is recently reported to be remarkably downregulated in a variety of tumours and served as a tumour suppressor. However, the functions and underlying mechanism of lncRNA BDNF-AS in CRC pathogenesis have not been reported yet. Our study is the first to demonstrate the effect of lncRNA BDNF-AS in CRC and revealed that lncRNA BDNF-AS expression is negatively correlated with the aggressive biological behaviour of CRC. Further investigation demonstrated that lncRNA BDNF-AS functioned as a tumour suppressor in CRC progression by suppressing GSK-3ß expression through binding to EZH2 and H3K27me3 with the GSK-3ß promoter, shedding light on the diagnosis and therapy for CRC.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Movimento Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , RNA Longo não Codificante/genética , Proliferação de Células/genética , Glicogênio Sintase Quinase 3 beta/biossíntese , Glicogênio Sintase Quinase 3 beta/deficiência , Células HCT116 , Humanos , RNA Longo não Codificante/metabolismo
17.
Environ Pollut ; 252(Pt A): 39-50, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146237

RESUMO

Exposure to ultrafine particulate matter (PM0.1) is positively associated with the etiology of different acute and chronic disorders; however, the in-depth biological imprints that link these submicron particles with the disturbances in the epigenomic machinery are not well defined. Earlier, we showed that exposure to these particles causes significant disturbances in the mitochondrial machinery and triggers PI-3-kinase mediated DNA damage responses. In the present study, we aimed to further understand the epigenomic insights of the ultrafine PM exposure. The higher levels of intracellular reactive oxygen species and depleted Nrf-2 in ultrafine PM exposed cells reconfirmed its potential to induce oxidative stress. Importantly, the observed increase in the levels of NF-κß and associated cytokines among exposed cells suggested the activation of NF-κß mediated inflammatory loop which potentially serves as a platform for initiating epigenetic insinuations. This fact was strongly supported by the altered miRNA expression profile of the ultrafine PM exposed cells. These NF-κß induced miRNA alterations were also found to be associated with other epigenetic targets as the exposed cells showed higher expression levels of DNA methyltransferases which positively corresponded with the global changes in DNA methylation levels. Upon further analysis, significant alterations in histone code were also reported in ultrafine PM exposed cells. Conclusively our results suggested that NF-κß acts as an inflammatory switch that possesses the potential to induce genome-wide epigenetic modification upon ultrafine PM exposure.


Assuntos
Metilação de DNA/efeitos dos fármacos , Epigênese Genética/genética , Linfócitos/metabolismo , NF-kappa B/metabolismo , Material Particulado/toxicidade , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dano ao DNA/efeitos dos fármacos , Metilases de Modificação do DNA/biossíntese , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Mitocôndrias/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Tamanho da Partícula , Material Particulado/análise , Fosfatidilinositol 3-Quinase/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Anticancer Res ; 39(5): 2361-2367, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092428

RESUMO

BACKGROUND/AIM: Previous studies have documented that osteoprotegerin (OPG) is involved in the development and progression of several human malignancies. However, OPG has also been shown to act as a tumor suppressor. The aim of this study was to examine the expression status of OPG in ovarian carcinoma cells and investigate the underlying mechanism responsible for alterations in OPG expression. MATERIALS AND METHODS: The expression levels of OPG mRNA and protein were assessed in human ovarian carcinoma cell lines. The methylation status of the OPG promoter region was determined using the bisulfite pyrosequencing technique. The effects of demethylation on OPG expression were also analyzed. RESULTS: The human ovarian carcinoma cell lines, SW 626, OVCAR-3, ES-2, TOV-112D, and TOV-21G, expressed significantly lower levels of OPG mRNA and protein than the normal human ovarian epithelial cell line, HS823.Tc. Moreover, three CpG sites in the OPG promoter region were highly methylated in the SW 626, OVCAR-3, ES-2, and TOV-112D ovarian carcinoma cell lines compared to normal control cells. Furthermore, in all the examined ovarian carcinoma cell lines, treatment with the demethylating agent, 5-aza-2-deoxycytidine, resulted in significantly increased expression levels of OPG mRNA and protein compared to the respective pre-treatment levels. CONCLUSION: OPG expression was down-regulated in the studied ovarian carcinoma cells compared to the normal control cells, while demethylation significantly restored OPG expression in the OPG-down-regulated cell lines. Our results suggest that OPG down-regulation in ovarian carcinoma occurs, at least partly, through epigenetic repression, suggesting its involvement in ovarian carcinogenesis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/genética , Metilação de DNA/genética , Osteoprotegerina/genética , Carcinogênese/genética , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Epigênese Genética/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Regiões Promotoras Genéticas
19.
Mol Cell ; 74(4): 651-663.e8, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-30954402

RESUMO

Accumulating evidence supports the role of the DNA damage response (DDR) in the negative regulation of tumorigenesis. Here, we found that DDR signaling poises a series of epigenetic events, resulting in activation of pro-tumorigenic genes but can go as far as reactivation of the pluripotency gene OCT4. Loss of DNA methylation appears to be a key initiating event in DDR-dependent OCT4 locus reactivation although full reactivation required the presence of a driving oncogene, such as Myc and macroH2A downregulation. Using genetic-lineage-tracing experiments and an in situ labeling approach, we show that DDR-induced epigenetic reactivation of OCT4 regulates the resistance to chemotherapy and contributes to tumor relapse both in mouse and primary human cancers. In turn, deletion of OCT4 reverses chemoresistance and delays the relapse. Here, we uncovered an unexpected tumor-promoting role of DDR in cancer cell reprogramming, providing novel therapeutic entry points for cancer intervention strategies.


Assuntos
Carcinogênese/genética , Metilação de DNA/genética , Neoplasias/genética , Fator 3 de Transcrição de Octâmero/genética , Animais , Reprogramação Celular/genética , Dano ao DNA/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Humanos , Camundongos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Recidiva , Transdução de Sinais/genética
20.
BMC Biol ; 17(1): 30, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30967153

RESUMO

BACKGROUND: Epigenetic mechanisms play fundamental roles in brain function and behavior and stressors such as social isolation can alter animal behavior via epigenetic mechanisms. However, due to cellular heterogeneity, identifying cell-type-specific epigenetic changes in the brain is challenging. Here, we report the first use of a modified isolation of nuclei tagged in specific cell type (INTACT) method in behavioral epigenetics of Drosophila melanogaster, a method we call mini-INTACT. RESULTS: Using ChIP-seq on mini-INTACT purified dopaminergic nuclei, we identified epigenetic signatures in socially isolated and socially enriched Drosophila males. Social experience altered the epigenetic landscape in clusters of genes involved in transcription and neural function. Some of these alterations could be predicted by expression changes of four transcription factors and the prevalence of their binding sites in several clusters. These transcription factors were previously identified as activity-regulated genes, and their knockdown in dopaminergic neurons reduced the effects of social experience on sleep. CONCLUSIONS: Our work enables the use of Drosophila as a model for cell-type-specific behavioral epigenetics and establishes that social environment shifts the epigenetic landscape in dopaminergic neurons. Four activity-related transcription factors are required in dopaminergic neurons for the effects of social environment on sleep.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Drosophila melanogaster/genética , Epigênese Genética/genética , Genética Comportamental/métodos , Meio Social , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Epigenômica/métodos , Masculino , Modelos Animais , Sono/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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