metilação dna_tópicos.pdf
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EPIGENTICA
Augusto Faria AndradeJaqueline Carvalho de Oliveira
Sarah Blima Paulino Leite
Tpicos Especiais em Gentica I
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Epigentica
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Modificao herdvel sem mudanas na
seqncia do DNA
Epigentica
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Epigenoma
Conjunto das modificaes epigenticas
Caracterstico ao tipo celular
Mecanismo diferenciao
Regulao da acessibilidade da informao genticapara a maquinaria celular
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Mecanismos Epigenticos
Modificaes no DNA (metilao)
Modificaes de histonas
Mecanismos baseados em microRNAs
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Falhas na manuteno epigenticas resultam naativao ou inibio imprpria levando aodesenvolvimento de patologias
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Metilao do DNA
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Adio grupo metil (CH 3) ao carbono 5 da citosina formando5-metilcitosina;
Padro de metilao estabelecido durante odesenvolvimento embrionrio e mantido durante a vida doindivduo idade e dieta .
Reao catalisada pelas DNA metiltransferases (DNMTs);
Classes principais: DNMT1, DNMT2 e DNMT3;
DNMT1 - processo de metilao que ocorre durante a divisocelular mittica, copiando o padro de metilao da fita
original
DNMT2 - atividade metiltransferase de tRNA
DNMT3 (A e B) - est relacionada aquisio de metilao
de DNA de novo.
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Citosinas adjacentes a uma guanina so passveis de seremmetiladas;
Ilhas CpG - so regies com cerca de 1 kb de tamanho, queocorrem em mdia a cada 100 kb
Dinucleotdeos geralmente presentes na regio 5UTR dosgenes, especialmente no promotor e no primeiro xon;
Impedindo a ligao de fatores de transcrio a seus stiospresentes na regio reguladora dos genes;
Em clulas tumorais, ametilao das ilhas CpG mais frequente.
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Cncer
Epigeneticamente - demetilao global do DNA ehipermetilao localizada de genes especficos;
Silenciamento gnico - genes de reparo ou genessupressores de tumores;
Inibidores de metilao - usado para vrios tipos de cncer.
Procana : provoca hipometilao global do DNA, aumenta a
eficcia de diversos quimioterpicos, menos efeitos colateraisdo que os nucleosdeos.
Procainamida : inibidor no competitivo das enzimas DNAmetiltransferases. Eficaz no cncer de prstata.
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MetiladoNo-Metilado
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Anlogos de Desoxinucleosdeos Inibidores das DNA metiltransferases.
5,6-dihidro-5-azacitidina, decitabina procana,
5-azacitidina, 5-aza-20-deoxicitidina.
Ao antineoplsica comprovada, efeitos citotxicos;
Inibe a proliferao celular, atrasa o ciclo em G2/M e induzapoptose;
FDA aprovou o anlogo 5-azacitidina para o tratamento desndromes mielodisplsicas.
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Anlogos de desoxinucleosdeos como 5-aza-2'-desoxicitidina soconvertidos em trifosfato e incorporados no lugar da citosina no DNA,formando ligaes covalentes com as DNMTs, resultando na depleodas enzimas ativas e na demetilao do DNA (EGGER et al ., 2004).
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Outras doenas
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Histonas
Pequenas protenas compostas por um domnio globular euma cauda aminoterminal flexvel
Formas cannicas e variantes
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Modificao de Histonas
Controle epigentico da expresso gnica Cauda N-terminal 60 resduos 8 tipos de modificaes
KOUZARIDES, 2007
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Metilao e Acetilao
Metilao
Efeito depende da histona e do
resduo metilado: H3 nas lisinas 4, 36 e 79 abrem acromatina, ativando a transcrio
H3 nas lisinas 9 e 27 facilitam ametilao do DNA e silenciamento degenes
Acetilao Ativa a cromatina e permite o acesso
de outras protenas ao DNA Hipoacetilao relacionada a regiestranscricionalmente inativas
SHARMA, 2010
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Interao entre Metilao do DNAe Modificao de Histonas
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Mecanismo de silenciamentoepigentico
SHARMA, 2010
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Cdigo de Histonas
Hiptese sugere que a multiplicidade de combinaesformam um cdigo que pode ser lido e interpretado
SHARMA, 2010
A presena de uma dada modificao pode facilitar ouimpedir que uma segunda modificao acontea.
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Enzimas
HMT (Histona metiltransferase)
HAT (Histona acetiltransferase)
HDM (Histona demetilase)
HDAC (Histona deacetilase)
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Modificaes no-covalentes
Remodeladores de nucleossomos dependentes de ATP Regies livres de nucleossomos maquinaria de transcrio
Ocluso do stio de incio da transcrio represso gnica
Incorporao de histonas variantes
CenH3
H3.3
H2A.Z
H2A.X
Promotores genes ativosv Acetilao genes ativos na eucromatina
v Ubiquitinao heterocromatina facultativa
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Domnios bivalentes em clulasembrionrias
SHARMA, 2010
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Anormalidades no padro demodificao de histonas
O desequilbrio acetilao/desacetilao das histonas emregies promotoras contribui para a desregulao da
expresso gnica
Tais perdas de acetilao levam a represso gnica
HDAC so freqentemente encontradas superexpressas emvrios tipos de cncer
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Terapias com iHDAC
Inibidores de histonas deacetilases (iHDAC) tm emergidocomo uma nova classe de agentes anticncer.
Notveis efeitos na proliferao da clula tumoral, na mortecelular programada, na diferenciao e angiognese tumoralin vitro e in vivo (MAYO et al., 2003; INSINGA et al., 2005).
Estudo com a atividade sinrgica de inibidores de metilaodo DNA e de HDAC demonstrou uma grande reduo naformao de tumor em pulmes de camundongos quandotratados com fenilbutirato e 5-Aza-CdR juntos (BELINSKY etal., 2003).
MENDITI; KANG, 2007
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microRNAs
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microRNAs
De 17 a 23 nucleotdeos
Mais de 4000 miRNAs
Cerca de 800 em humanos
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microRNAs x Epigentica
2-3% dos genes: proliferao, diferenciao e apoptose.
miRNAMecanismosEpigenticos
MecanismosEpigenticos
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Dicer necessria para a formao de heterocromatina
Tratamento com RNAse diminui metilao de histonas
microRNAs x Epigentica
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Inativao do X
XIST = RNA no codificante
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11p15
Imprinting
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Epigentica
Conjunto (met, hist, micro)
Melhor entendimento
Manipulao
Reestabelecimento
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Obrigada
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