Modificações em marcas epigenéticas em histonas ao longo da gênese do melanoma
Arquivos
Data
2011
Autores
Meliso, Fabiana Marcelino 
Orientadores
Jasiulionis, Miriam Galvonas
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Entre os principais transtornos mundiais, o cancer permanece como a segunda doenca responsavel pelo maior numero de mortes no mundo e o melanoma e, cada vez mais, um dos tipos mais preocupantes de tumor. Os tumores, como amplamente estudado, estao relacionados a fatores geneticos e epigeneticos, entretanto, ate o momento, nao esta claro quais sao os fatores que levam ao estabelecimento de padroes epigeneticos aberrantes associados tanto ao inicio quanto a progressao tumoral. Recentes estudos tem demonstrado que alteracoes no microambiente celular, assim como o estresse oxidativo, sao importantes fatores que levam ao estabelecimento de caracteristicas neoplasicas. Metilacao de DNA e modificacoes pos-traducionais em histonas sao os mecanismos epigeneticos mais estudados. Embora haja estudos sobre metilacao de DNA aberrante em melanomas, ainda sao escassos os estudos sobre marcas em histonas nestes tumores. Nesse sentido, utilizando um modelo murino de transformacao maligna de melanocitos associado a condicoes sustentadas de estresse, esse trabalho teve por objetivo identificar padroes epigeneticos aberrantes associados a diferentes fases da genese do melanoma. Foram observadas variacoes em marcas de histonas relacionadas a ativacao ou repressao genica nas primeiras etapas e ao longo da progressao maligna, com indicios de cromatina aberta nos estagios intermediarios da transformacao. Da mesma forma, identificamos alteracoes em componentes da maquinaria epigenetica ao longo da transformacao maligna dos melanocitos. Alem disso, dados ainda preliminares indicam associacao diferencial de sequencias de DNA a desacetilase de histonas Sirt1 apos submeter os melanocitos a situacao de estresse sustentado, o que pode indicar um papel de Sirt1 no estabelecimento de padroes epigeneticos aberrantes. Finalmente, esse trabalho mostra mudancas dinamicas tanto em componentes da maquinaria quanto em marcas epigeneticas ao longo da genese do melanoma e ainda sugere reprogramacao epigenetica e aquisicao de caracteristicas de pluripotencia nos estagios que precedem a aquisicao do fenotipo maligno pelos melanocitos
Among the major disorders in the world, cancer remains the second disease responsible for more deaths in the world and melanoma is one of the most aggressive types of tumor. The tumors, as widely studied, are related to genetic and epigenetic factors, however, until this moment it is not clear which are the factors that lead to the establishment of aberrant epigenetic patterns associated with both the initiation and progression of the tumor. Recent studies have shown that changes in cellular microenvironment, as well as oxidative stress, are important factors that lead to the establishment of neoplastic features. DNA methylation and post-translational modifications in histones are the most studied epigenetic mechanisms. Although there are studies about aberrant DNA methylation in melanomas, there are still few studies of histone marks in these tumors. In this sense, using a murine model of malignant transformation of melanocytes associated with conditions of sustained stress, this study aimed to identify aberrant epigenetic patterns associated with different stages of the genesis of melanoma. Changes were observed in histone marks related to gene activation or repression in the early stages and along malignant progression, with indications of open chromatin in the intermediate stages of transformation. Likewise, we identified changes in epigenetic machinery components along the malignant transformation of melanocytes. Furthermore, preliminary data indicate differential association of DNA sequences to histone deacetylases SIRT1 after submitting the melanocytes to the situation of sustained stress, which may indicate a role of SIRT1 in the establishment of aberrant epigenetic patterns. Finally, this study shows dynamic changes in both components of the machinery and epigenetic marks during melanoma genesis and further suggests epigenetic reprogramming and acquisition of pluripotency characteristics in the stages that precede the acquisition of malignant phenotype by melanocytes.
Among the major disorders in the world, cancer remains the second disease responsible for more deaths in the world and melanoma is one of the most aggressive types of tumor. The tumors, as widely studied, are related to genetic and epigenetic factors, however, until this moment it is not clear which are the factors that lead to the establishment of aberrant epigenetic patterns associated with both the initiation and progression of the tumor. Recent studies have shown that changes in cellular microenvironment, as well as oxidative stress, are important factors that lead to the establishment of neoplastic features. DNA methylation and post-translational modifications in histones are the most studied epigenetic mechanisms. Although there are studies about aberrant DNA methylation in melanomas, there are still few studies of histone marks in these tumors. In this sense, using a murine model of malignant transformation of melanocytes associated with conditions of sustained stress, this study aimed to identify aberrant epigenetic patterns associated with different stages of the genesis of melanoma. Changes were observed in histone marks related to gene activation or repression in the early stages and along malignant progression, with indications of open chromatin in the intermediate stages of transformation. Likewise, we identified changes in epigenetic machinery components along the malignant transformation of melanocytes. Furthermore, preliminary data indicate differential association of DNA sequences to histone deacetylases SIRT1 after submitting the melanocytes to the situation of sustained stress, which may indicate a role of SIRT1 in the establishment of aberrant epigenetic patterns. Finally, this study shows dynamic changes in both components of the machinery and epigenetic marks during melanoma genesis and further suggests epigenetic reprogramming and acquisition of pluripotency characteristics in the stages that precede the acquisition of malignant phenotype by melanocytes.
Descrição
Citação
MELISO, Fabiana Marcelino. Modificações em marcas epigenéticas em histonas ao longo da gênese do melanoma. Tese (Doutorado em Ciências) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2011.