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Controle genético e epigenético da expressão heteromórfica de regiões organizadoras do nucléolo em Crotalaria retusa L. (Leguminosae-Papilionoideae); Genetic and epigenetic control of the heteromorphic expression of nucleolus organizer regions in Crotalaria retusa L. (Leguminosae-Papilionoideae)

Fuchs, Maria Cecília Perantoni
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 16/09/2009 Português
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O presente trabalho teve por objetivo compreender e analisar os mecanismos genéticos e epigenéticos da expressão diferencial de regiões organizadoras do nucléolo - RONs através do estudo de dois acessos (CRT-1 e CRT-2) de Crotalaria retusa. O acesso CRT-1 é uma cultivar, enquanto que o acesso CRT-2 é proveniente de uma população periférica da orla marítima de Ilhéus BA. Por serem temporalmente e espacialmente separados, acredita-se que os acessos foram submetidos a pressões seletivas diferentes, resultando em alterações dos padrões epigenéticos, principalmente nas RONs. Para o desenvolvimento deste trabalho foram realizadas medidas cromossômicas e nucleolares a partir de células coradas pelo método de Feulgen e por nitrato de prata, coloração com fluorocromos específicos às regiões cromossômicas ricas em nucleotídeos GC e AT, mapeamento físico dos locos de DNA ribossômico 45S por hibridação in situ fluorescente, análise qualitativa e quantitativa de modificações pós-traducionais de histonas por Western blot e eletroforese bidimensional de extrato protéico radicular com enfoque em proteínas envolvidas nos mecanismos epigenéticos. As análises citológicas demonstraram uma grande semelhança nos cariótipos dos dois acessos...

Efeitos do tratamento com selênio no crescimento e marcas epigenéticas de células de adenocarcinoma mamário humano MCF-7; Effects of selenium treatment on growth and epigenetic marks of MCF-7 human breast adenocarcinoma cells

Miranda, Juliana Xavier de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 05/11/2012 Português
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O câncer de mama representa problema mundial de saúde pública e a causa mais frequente de morte por câncer entre as mulheres. A identificação de agentes moduladores de marcas epigenéticas, tais como metilação global do DNA e modificações pós-tradução em histonas, compreende alternativa promissora para estabelecimento de estratégias de controle da carcinogênese mamária. Dentre os nutrientes, o elemento traço essencial selênio (Se) pode ser destacado como agente dietético com potencial anti-câncer de mama e que poderia atuar modulando processos epigenéticos. Entretanto seus mecanismos de ação são pouco elucidados. Este estudo objetivou, assim, identificar efeitos do tratamento com selênio no crescimento e marcas epigenéticas de células de adenocarcinoma mamário humano MCF-7. Células MCF-7, positivas para o receptor de estrógeno, foram tratadas com ácido metilselenínico (MSA) ou selenito de sódio (ST) por diferentes tempos e em diferentes concentrações. Foram avaliados: padrão de proliferação (ensaio cristal violeta) e viabilidade celular (método de exclusão azul de tripan); integridade de membrana plasmática (citometria de fluxo); níveis de fragmentação do DNA (citometria de fluxo), distribuição das fases do ciclo celular (citometria de fluxo); apoptose (citometria de fluxo/ marcação dupla com Anexina V - Iodeto de propídio); níveis de lisina 9 acetilada (H3K9ac) e trimetilada (H3K9me3) em histona H3; níveis de lisina 16 acetilada (H4K16ac) em histona H4 (Western blot); padrão de metilação global do DNA (HPLC-DAD); expressão de gene supressor de tumor (RASSF1a; qPCR) e padrão de metilação da região promotora (RASSF1a e RARβ; MS-PCR); expressão da enzima DNA metilstransferase 1 (DNMT1) (Western Blotting). Comparado ao grupo controle de células não tratadas (GC)...

Efeito do ácido docosahexaenoico (DHA) sobre eventos epigenéticos em diferentes linhagens de câncer de mama; Effect of docosahexaenoic acid (DHA) on epigenetic events in diferente breast cancer cell lines

Castro, Rita de Cássia Borges de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 09/09/2013 Português
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Alterações epigenéticas, como metilação do DNA e modificações pós traducionais em histonas, tem importante papel na carcinogênese mamária. A modulação de eventos epigenéticos constitui relevante alvo terapêutico, devido ao seu caráter reversível. Experimentalmente, o ácido docosahexaenoico (DHA), um membro da família dos ácidos graxos ômega-3, é capaz de diminuir proliferação, induzir morte celular e diminuir o potencial invasivo de células tumorais de mama. No entanto, os mecanismos antitumorais do DHA e sua capacidade de modular eventos epigenéticos ainda não estão totalmente elucidados. Nosso objetivo foi verificar, in vitro, a ação do DHA em eventos epigenéticos em diferentes linhagens de carcinoma mamário humano. Três linhagens celulares de câncer de mama (MDA-MB-231, SKBR-3 e MCF-7) foram tratadas durante 72 horas com 100 ?M de DHA ou etanol (controle). As modificações pós traducionais em histonas, acetilação no resíduo de lisina 9 da histona 3 (H3K9ac) e no resíduo 16 da histona 4 (H4K16ac), bem como trimetilação no resíduo de lisina 9 da histona 3 (H3K9me3) e no resíduo de lisina 27 da histona 3 (H3K27me3) foram avaliadas pela técnica de western blot. A análise da expressão do genes RASSF1A...

Avaliação do efeito de moduladores epigenéticos na biossíntese de produtos naturais em fungos; Evaluation of the effect of epigenetic modifiers in the biosynthesis of fungal natural products.

Almeida, Marília Oliveira de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 02/07/2014 Português
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A manipulação seletiva de alvos epigenéticos usando pequenas moléculas inibidoras das enzimas histona-desacetilases (HDACs) e DNA metiltransferases (DNMTs) é uma estratégia para estimular a expressão das vias biossintéticas e a produção de novos metabólitos secundários em fungos. Neste trabalho, inibidores de histonadesacetilases (butirato de sódio, ácido hidroxâmico suberoilanilida e ácido valproico) e inibidores de DNA metiltransferases (5-azacitidina, hidralazina, procaína e procainamida) foram suplementados em culturas líquidas e sólidas dos fungos endofíticos Fusarium oxysporum SS46, Hyphodermella corrugata FLe8.2 e Chaetomium globosum VR10, das linhagens comerciais Fusarium oxysporum ATCC MYA 4623 e Chaetomium globosum ATCC 56726 e do fitopatógeno Botrytis cinerea B0510. O fungo endofítico H. corrugata FLe8.2, em meio PDB, produziu o composto 2-(2-metoxifenil)-4H-piran-4-ona, e sua cultura em meio Czapek suplementada com hidralazina levou ao isolamento de 3-metil-1,2,4-triazolo[3,4-a]-ftalazina. O tratamento de F. oxysporum SS46 e F. oxysporum ATCC MYA 4623 com hidralazina em meio Czapek levou ao isolamento de um novo composto, 2H-[1,2,4]triazino[3,4- a]-ftalazina. Nestas culturas houve biotransformação da hidralazina pelos fungos...

Epigenetic mechanisms in penile carcinoma

Kuasne, Hellen; Marchi, Fabio Albuquerque; Rogatto, Silvia Regina; de Syllos Cólus, Ilce Mara
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 10791-10808
Português
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Penile carcinoma (PeCa) represents an important public health problem in poor and developing countries. Despite its unpredictable behavior and aggressive treatment, there have only been a few reports regarding its molecular data, especially epigenetic mechanisms. The functional diversity in different cell types is acquired by chromatin modifications, which are established by epigenetic regulatory mechanisms involving DNA methylation, histone acetylation, and miRNAs. Recent evidence indicates that the dysregulation in these processes can result in the development of several diseases, including cancer. Epigenetic alterations, such as the methylation of CpGs islands, may reveal candidates for the development of specific markers for cancer detection, diagnosis and prognosis. There are a few reports on the epigenetic alterations in PeCa, and most of these studies have only focused on alterations in specific genes in a limited number of cases. This review aims to provide an overview of the current knowledge of the epigenetic alterations in PeCa and the promising results in this field. The identification of epigenetically altered genes in PeCa is an important step in understanding the mechanisms involved in this unexplored disease. © 2013 by the authors; licensee MDPI...

Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease

Relton, Caroline L; Davey Smith, George
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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The burgeoning interest in the field of epigenetics has precipitated the need to develop approaches to strengthen causal inference when considering the role of epigenetic mediators of environmental exposures on disease risk. Epigenetic markers, like any other molecular biomarker, are vulnerable to confounding and reverse causation. Here, we present a strategy, based on the well-established framework of Mendelian randomization, to interrogate the causal relationships between exposure, DNA methylation and outcome. The two-step approach first uses a genetic proxy for the exposure of interest to assess the causal relationship between exposure and methylation. A second step then utilizes a genetic proxy for DNA methylation to interrogate the causal relationship between DNA methylation and outcome. The rationale, origins, methodology, advantages and limitations of this novel strategy are presented.

Potential Role of Epigenetic Mechanisms in the Regulation of Drug Metabolism and Transport

Ingelman-Sundberg, Magnus; Zhong, Xiao-Bo; Hankinson, Oliver; Beedanagari, Sudheer; Yu, Ai-Ming; Peng, Lai; Osawa, Yoichi
Fonte: The American Society for Pharmacology and Experimental Therapeutics Publicador: The American Society for Pharmacology and Experimental Therapeutics
Tipo: Artigo de Revista Científica
Português
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This is a report of a symposium on the potential role of epigenetic mechanisms in the control of drug disposition sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2013 meeting in Boston, MA, April 21, 2013. Epigenetics is a rapidly evolving area, and recent studies have revealed that expression of drug-metabolizing enzymes and transporters is regulated by epigenetic factors, including histone modification, DNA methylation, and noncoding RNAs. The symposium speakers provided an overview of genetic and epigenetic mechanisms underlying variable drug metabolism and drug response, as well as the implications for personalized medicine. Considerable insight into the epigenetic mechanisms in differential regulation of the dioxin-inducible drug and carcinogen-metabolizing enzymes CYP1A1 and 1B1 was provided. The role of noncoding microRNAs in the control of drug metabolism and disposition through targeting of cytochrome P450 (P450) enzymes and ATP-binding cassette membrane transporters was discussed. In addition, potential effects of xenobiotics on chromatin interactions and epigenomics, as well as the possible role of long noncoding RNAs in regulation of P450s during liver maturation were presented.

Epigenetic Regulation of ADME-Related Genes: Focus on Drug Metabolism and Transport

Zhong, Xiao-bo; Leeder, J. Steven
Fonte: The American Society for Pharmacology and Experimental Therapeutics Publicador: The American Society for Pharmacology and Experimental Therapeutics
Tipo: Artigo de Revista Científica
Português
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Epigenetic regulation of gene expression refers to heritable factors that are functionally relevant genomic modifications but that do not involve changes in DNA sequence. Examples of such modifications include DNA methylation, histone modifications, noncoding RNAs, and chromatin architecture. Epigenetic modifications are crucial for packaging and interpreting the genome, and they have fundamental functions in regulating gene expression and activity under the influence of physiologic and environmental factors. Recently, epigenetics has become one of the fastest-growing areas of science and has now become a central issue in biologic studies of development and disease pathogenesis. The interest in epigenetics is also true for studies of drug metabolism and transport. In this issue of Drug Metabolism and Disposition, a series of articles is presented to demonstrate the role of epigenetic factors in regulating the expression of genes involved in drug absorption, distribution, metabolism, and excretion in organ development, tissue-specific gene expression, sexual dimorphism, and in the adaptive response to xenobiotic exposure, both therapeutic and toxic. The articles also demonstrate that, in addition to genetic polymorphisms, epigenetics may also contribute to wide interindividual variations in drug metabolism and transport. Identification of functionally relevant epigenetic biomarkers in human specimens has the potential to improve prediction of drug responses based on patient’s epigenetic profiles.

Optical control of mammalian endogenous transcription and epigenetic states

Brigham, Mark Daniel
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
Português
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The dynamic nature of gene expression enables cellular programming, homeostasis and environmental adaptation in living systems. Dissection of causal gene functions in cellular and organismal processes therefore necessitates approaches that enable spatially and temporally precise modulation of gene expression. Recently, a variety of microbial and plant-derived light-sensitive proteins have been engineered as optogenetic actuators, enabling high-precision spatiotemporal control of many cellular functions. However, versatile and robust technologies that enable optical modulation of transcription in the mammalian endogenous genome remain elusive. Here we describe the development of light-inducible transcriptional effectors (LITEs), an optogenetic two-hybrid system integrating the customizable TALE DNA-binding domain with the light-sensitive cryptochrome 2 protein and its interacting partner CIB1 from Arabidopsis thaliana. LITEs do not require additional exogenous chemical cofactors, are easily customized to target many endogenous genomic loci, and can be activated within minutes with reversibility. LITEs can be packaged into viral vectors and genetically targeted to probe specific cell populations. We have applied this system in primary mouse neurons...

Targeting Transcription Factor SALL4 in Acute Myeloid Leukemia by Interrupting Its Interaction with an Epigenetic Complex

Gao, Chong; Dimitrov, Todor; Yong, Kol Jia; Tatetsu, Hiro; Jeong, Ha-Won; Luo, Hongbo; Bradner, James Elliott; Tenen, Daniel Geoffrey; Chai, Li
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Português
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An exciting recent approach to targeting transcription factors in cancer is to block formation of oncogenic complexes. We investigated whether interfering with the interaction of the transcription factor SALL4, which is critical for leukemic cell survival, and its epigenetic partner complex represents a novel therapeutic approach. The mechanism of SALL4 in promoting leukemogenesis is at least in part mediated by its repression of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through its interaction with a histone deacetylase (HDAC) complex. In this study, we demonstrate that a peptide can compete with SALL4 in interacting with the HDAC complex and reverse its effect on PTEN repression. Treating SALL4-expressing malignant cells with this peptide leads to cell death that can be rescued by a PTEN inhibitor. The antileukemic effect of this peptide can be confirmed on primary human leukemia cells in culture and in vivo, and is identical to that of down-regulation of SALL4 in these cells using an RNAi approach. In summary, our results demonstrate a novel peptide that can block the specific interaction between SALL4 and its epigenetic HDAC complex in regulating its target gene, PTEN. Furthermore, targeting SALL4 with this approach could be an innovative approach in treating leukemia.

The role of epigenetic modifications in prostate tumourigenesis.

Chiam, Karen HuiQin
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2010 Português
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Prostate cancer is the second-leading cause of cancer death in Australian men. Current therapies for advanced prostate cancer are not curative and most patients eventually develop castrate resistant prostate cancer. Epigenetic modifications are heritable and reversible biochemical changes of the chromatin that regulate gene expression and are important in prostate tumourigenesis. There is also evidence that excess foetal nutrition is associated with increased risk of developing prostate cancer. Hence, the aims of this thesis were to determine the involvement of epigenetic modifications in: the early origin of prostate cancer, prostate cancer progression, as prognostic and therapeutic targets in prostate cancer. The first aim of this thesis was to use a rodent model to determine if a maternal high fat diet (MHFD) is associated with increased risk of prostate cancer in offspring. Offspring exposed to a MHFD had increased incidence of prostate abnormalities compared to offspring exposed to a maternal control diet. GSTP1 is hypermethylated and silenced in human prostate cancer and was decreased in these offspring prostates. The MHFD altered the male offspring prostates microRNA expression and provided insights of possible underlying mechanisms that support a link between MHFD and risk of prostate cancer in adult offspring. The second aim was to investigate if specific histone modifications H3K18Ac and H3K4diMe were prognostic markers for prostate cancer. High levels of H3K18Ac and H3K4diMe were associated with increased risk of prostate cancer relapse respectively. To further investigate the underlying mechanisms...

Epigenetic rather than genetic factors may explain phenotypic divergence between coastal populations of diploid and tetraploid Limonium spp. (Plumbaginaceae) in Portugal

Rois, A.; Rodriguez Lopez, C.; Cortinhas, A.; Erben, M.; Espirito-Santo, D.; Wilkinson, M.; Caperta, A.
Fonte: BioMed Central Ltd. Publicador: BioMed Central Ltd.
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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Background: The genus Limonium Miller comprises annual and perennial halophytes that can produce sexual and/or asexual seeds (apomixis). Genetic and epigenetic (DNA methylation) variation patterns were investigated in populations of three phenotypically similar putative sexual diploid species (L. nydeggeri, L. ovalifolium, L. lanceolatum), one sexual tetraploid species (L. vulgare) and two apomict tetraploid species thought to be related (L. dodartii, L. multiflorum). The extent of morphological differentiation between these species was assessed using ten diagnostic morphometric characters. Results: A discriminant analysis using the morphometric variables reliably assigns individuals into their respective species groups. We found that only modest genetic and epigenetic differentiation was revealed between species by Methylation Sensitive Amplification Polymorphism (MSAP). However, whilst there was little separation possible between ploidy levels on the basis of genetic profiles, there was clear and pronounced interploidy discrimination on the basis of epigenetic profiles. Here we investigate the relative contribution of genetic and epigenetic factors in explaining the complex phenotypic variability seen in problematic taxonomic groups such as Limonium that operate both apomixis and sexual modes of reproduction. Conclusions: Our results suggest that epigenetic variation might be one of the drivers of the phenotypic divergence between diploid and tetraploid taxa and discuss that intergenome silencing offers a plausible mechanistic explanation for the observed phenotypic divergence between these microspecies. These results also suggest that epigenetic profiling offer an additional tool to infer ploidy level in stored specimens and that stable epigenetic change may play an important role in apomict evolution and species recognition.; Ana Sofia Róis...

EZH2 and KDM6A act as an epigenetic switch to regulate mesenchymal stem cell lineage specification

Hemming, S.; Cakouros, D.; Isenmann, S.; Cooper, L.; Menicanin, D.; Zannettino, A.; Gronthos, S.
Fonte: AlphaMed Press Publicador: AlphaMed Press
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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The methyltransferase, Enhancer of Zeste homology 2 (EZH2), trimethylates histone 3 lysine 27 (H3K27me3) on chromatin and this repressive mark is removed by lysine demethylase 6A (KDM6A). Loss of these epigenetic modifiers results in developmental defects. We demonstrate that Ezh2 and Kdm6a transcript levels change during differentiation of multipotential human bone marrow-derived mesenchymal stem cells (MSC). Enforced expression of Ezh2 in MSC promoted adipogenic in vitro and inhibited osteogenic differentiation potential in vitro and in vivo, whereas Kdm6a inhibited adipogenesis in vitro and promoted osteogenic differentiation in vitro and in vivo. Inhibition of EZH2 activity and knockdown of Ezh2 gene expression in human MSC resulted in decreased adipogenesis and increased osteogenesis. Conversely, knockdown of Kdm6a gene expression in MSC leads to increased adipogenesis and decreased osteogenesis. Both Ezh2 and Kdm6a were shown to affect expression of master regulatory genes involved in adipogenesis and osteogenesis and H3K27me3 on the promoters of master regulatory genes. These findings demonstrate an important epigenetic switch centered on H3K27me3 which dictates MSC lineage determination.; Sarah Hemming, Dimitrios Cakouros, Sandra Isenmann...

Pre-conditioning the epigenetic response to high vapor pressure deficit increases the drought tolerance of Arabidopsis thaliana

Tricker, P.; Rodriguez Lopez, C.; Hadley, P.; Wagstaff, C.; Wilkinson, M.
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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Epigenetic modification of the genome via cytosine methylation is a dynamic process that responds to changes in the growing environment. This modification can also be heritable. The combination of both properties means that there is the potential for the life experiences of the parental generation to modify the methylation profiles of their offspring and so potentially to “pre-condition” them to better accommodate abiotic conditions encountered by their parents. We recently identified high vapor pressure deficit (vpd)-induced DNA methylation at 2 gene loci in the stomatal development pathway and an associated reduction in leaf stomatal frequency.1 Here, we test whether this epigenetic modification pre-conditioned parents and their offspring to the more severe water stress of periodic drought. We found that 3 generations of high vpd-grown plants were better able to withstand periodic drought stress over 2 generations. This resistance was not directly associated with de novo methylation of the target stomata genes, but was associated with the cmt3 mutant’s inability to maintain asymmetric sequence context methylation. If our finding applies widely, it could have significant implications for evolutionary biology and breeding for stressful environments.; Penny J Tricker...

Evolution of a contagious cancer: epigenetic variation in Devil Facial Tumour Disease

Ujvari, B.; Pearse, A.M.; Peck, S.; Harmsen, C.; Taylor, R.; Pyecroft, S.; Madsen, T.; Papenfuss, A.T.; Belov, K.
Fonte: Royal Society of London Publicador: Royal Society of London
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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The emergence of Devil Facial Tumour Disease (DFTD), a highly contagious cancer, is driving Tasmanian devils (Sarcophilus harrisii) to extinction. The cancer is a genetically and chromosomally stable clonal cell line which is transmitted by biting during social interactions. In the present study, we explore the Devil Facial Tumour (DFT) epigenome and the genes involved in DNA methylation homeostasis. We show that tumour cells have similar levels of methylation to peripheral nerves, the tissue from which DFTD originated. We did not observe any strain or region-specific epimutations. However, we revealed a significant increase in hypomethylation in DFT samples over time (p < 0.0001). We propose that loss of methylation is not because of a maintenance deficiency, as an upregulation of DNA methyltransferase 1 gene was observed in tumours compared with nerves (p < 0.005). Instead, we believe that loss of methylation is owing to active demethylation, supported by the temporal increase in MBD2 and MBD4 (p < 0.001). The implications of these changes on disease phenotypes need to be explored. Our work shows that DFTD should not be treated as a static entity, but rather as an evolving parasite with epigenetic plasticity. Understanding the role of epimutations in the evolution of this parasitic cancer will provide unique insights into the role of epigenetic plasticity in cancer evolution and progression in traditional cancers that arise and die with their hosts.; Beata Ujvari...

Transgenerational inheritance or resetting of stress-induced epigenetic modifications: two sides of the same coin

Tricker, P.J.
Fonte: Frontiers Publicador: Frontiers
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
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The transgenerational inheritance of stress-induced epigenetic modifications is still controversial. Despite several examples of defense “priming” and induced genetic rearrangements, the involvement and persistence of transgenerational epigenetic modifications is not known to be general. Here I argue that non-transmission of epigenetic marks through meiosis may be regarded as an epigenetic modification in itself, and that we should understand the implications for plant evolution in the context of both selection for and selection against transgenerational epigenetic memory. Recent data suggest that both epigenetic inheritance and resetting are mechanistically directed and targeted. Stress-induced epigenetic modifications may buffer against DNA sequence-based evolution to maintain plasticity, or may form part of plasticity’s adaptive potential. To date we have tended to concentrate on the question of whether and for how long epigenetic memory persists. I argue that we should now re-direct our question to investigate the differences between where it persists and where it does not, to understand the higher order evolutionary methods in play and their contribution.; Penny J. Tricker

Epigenetic marks in the mature pollen of Quercus suber L. (Fagaceae)

Ribeiro, Teresa; Viegas, Wanda; Morais-Cecílio, Leonor
Fonte: Springer Publicador: Springer
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
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We have analysed the distribution of epigenetic marks for histone modifications at lysine residues H3 and H4, and DNA methylation, in the nuclei of mature pollen cells of the Angiosperm tree Quercus suber; a monoecious wind pollinated species with a protandrous system, and a long post-pollination period. The ultrasonic treatment developed for the isolation of pollen nuclei proved to be a fast and reliable method, preventing the interference of cell wall autofluorescence in the in situ immunolabelling assays. In contrast with previous studies on herbaceous species with short progamic phases, our results are consistent with a high level of silent (5-mC and H3K9me2) epigenetic marks on chromatin of the generative nucleus, and the prevalence of active marks (H3K9me3 and H4Kac) in the vegetative nucleus. The findings are discussed in terms of the pollination/fertilization timing strategy adopted by this plant species

Cooperative stabilization of the SIR complex provides robust epigenetic memory in a model of SIR silencing in Saccharomyces cerevisiae

Sneppen, K.; Dodd, I.B.
Fonte: Taylor and Francis Publicador: Taylor and Francis
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
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How alternative chromatin-based regulatory states can be made stable and heritable in order to provide robust epigenetic memory is poorly understood. Here, we develop a stochastic model of the silencing system in Saccharomyces cerevisiae that incorporates cooperative binding of the repressive SIR complex and anti-silencing histone modifications, in addition to positive feedback in Sir2 recruitment. The model was able to reproduce key features of SIR regulation of an HM locus, including heritable bistability, dependence on the silencer elements, and sensitivity to SIR dosage. We found that antisilencing methylation of H3K79 by Dot1 was not needed to generate these features, but acted to reduce spreading of SIR binding, consistent with its proposed role in containment of silencing. In contrast, cooperative inter-nucleosome interactions mediated by the SIR complex were critical for concentrating SIR binding around the silencers in the absence of barriers, and for providing bistability in SIR binding. SIR-SIR interactions magnify the cooperativity in the Sir2-histone deacetylation positive feedback reaction and complete a double-negative feedback circuit involving antisilencing modifications. Thus, our modelling underscores the potential importance of cooperative interactions between nucleosome-bound complexes both in the SIR system and in other chromatin-based complexes in epigenetic regulation.; Kim Sneppen and Ian B Dodd

Molecular Characterization of Genetic and Epigenetic Alterations in Gliomas

Duncan, Christopher Gentry
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2012 Português
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Glioma development and progression are driven by complex genetic alterations, including point mutations and gain or loss of genomic copy number, as well as epigenetic aberrations, including DNA methylation and histone modifications. However, the molecular mechanisms underlying the causes and effects of these alterations are poorly understood, and improved treatments are greatly needed. Here, we report a comprehensive evaluation of the recurrent genomic alterations in gliomas and further dissect the molecular effects of the most frequently-occurring genomic events. First, we performed a multifaceted genomic analysis to identify genes targeted by copy number alteration in glioblastoma, the most aggressive malignant glioma. We identify EGFR negative regulator, ERRFI1, as a glioblastoma-targeted gene within the minimal region of deletion in 1p36.23. Furthermore, we demonstrate that Aurora-A kinase substrate, TACC3, displays gain of copy number on 4p16.3 and is overexpressed in a grade-specific pattern. Next, using a gene targeting approach, we knocked-in a single copy of the most frequently observed point mutation in gliomas, IDH1R132H/WT, into a human cancer cell line. We show that heterozygous expression of the IDH1R132H allele is sufficient to induce the genome-wide alterations in DNA methylation characteristic of these tumors. Together...

Gene interaction networks and epigenetic control in health and disease transition; Redes de interação gênica e controle epigenético na transição saúde-doença

Azevedo, Hátylas; Bando, Silvia Yumi; Bertonha, Fernanda Bernardi; Moreira-Filho, Carlos Alberto
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; Formato: application/pdf
Publicado em 22/12/2015 Português
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A utilização de técnicas de alto desempenho (high-throughput) – como microarranjos de DNA e sequenciamento de nova geração - para o estudo do genoma em doenças complexas (i.e. causadas pela interação de fatores ambientais e genéticos) tem levado à produção massiva de dados e exigido o desenvolvimento de abordagens sistemáticas para a investigação de fenômenos biológicos. Essas abordagens centram-se na integração de dados (expressão gênica global, sequenciamento de DNA, interações proteína-proteína), além da caracterização, modelagem e predição das propriedades emergentes dos sistemas biológicos, ou seja, dos processos que ocorrem em células e tecidos como resposta a mudanças ambientais e genéticas. Um exemplo dessa abordagem é o estudo de alterações transcricionais através da obtenção de redes de co-expressão gênica, ou GCNs (acrônimo para gene coexpression network) e a visualização gráfica dessas redes complexas. A análise das GCNs permite a determinação da topologia dessas redes e a avaliação de como as interações gene-gene são alteradas na transição saúde-doença. É também possível associar as propriedades topológicas dessas redes com a organização funcional do genoma. Mudanças em propriedades das GCNs...