EPIGENETIQUE .I. Aerts
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EPIGENETIQUE Dr Isabelle AERTS-GAJDOS Institut Curie [email protected] Définition Chacune de nos cellules contient l’ensemble de notre patrimoine génétique 46 chromosomes 25 000 gènes Toutes nos cellules contiennent la même information MAIS une cellule de la peau ne ressemble en rien à un neurone une cellule du foie n’a pas les mêmes fonctions qu’une cellule du cœur deux jumeaux partagent le même génome ne sont jamais parfaitement identiques ! Dans ces exemples et dans bien d’autres, la clé du mystère se nomme "épigénétique". Definitions Definitions Modifications épigénétiques Modifications chimiques qui se superposent au génotype pour former un epigénotype Nature des modifications epigénétiques Methylation ADN Modifications des histones Partie NH2 terminale des histones constitutant le nucleosome ADN Octamère d’histones H2A, H2B, H3, H4 Epigénétique et cancer Dérégulation épigénétique Altération DNA methylation Hypomethylation Identification dans hémopathies de mutation dans les DNMT DNA Hydroxymethylation TET Mutations dans des hémopathies Epigénétique et cancer Modifications au niveau des histones Acetylation Acetyl transferase : KAT Mutations dans des hémopathies Readers : Bromodomaines Desacetylation HDAC Methylation KMT Hémopathies, medulloblastome Démethylation LSD1 Complexes intervenant dans le remodelage de a chromatine SW1/SNF ARID BRG1 Tumeur rhabdoide Oncogenic chromatin writers EZH2 Catalyzed Chromatin Remodeling • EZH2 is the catalytic subunit of the multi-protein PRC2 (polycomb repressive complex 2) • PRC2 is the only human protein methyltransferase that can methylate H3K27 – Catalyzes mono-, di- and tri-methylation of H3K27 – H3K27me3 is a transcriptionally repressive histone mark • H3K27 is the only significant substrate for PRC2 • Aberrant trimethylation of H3K27 is oncogenic in a broad spectrum of human cancers EZH2 H3K27 EZH2 H3K27me EZH2 H3K27me2 H3K27me3 Gene Transcription Chase 2011 17 Antagonism of PRC2 and SWI/SNF-Dependent Chromatin Remodeling Regulates Pluripotency Stem or Progenitor Cells Highly dependent on SWI/SNF EZH2 activity PRC2 INI1 EZH2 SMARCA4 PRC2 target genes Stem cell programs Self-renewal and Block in differentiation Adapted from Wilson 2010 18 EZH2 Activity Is Down-regulated as Progenitor Cells Become Differentiated Stem or Progenitor Cells Highly dependent on EZH2 activity SWI/SNF Differentiated Cells EZH2 Activity PRC2 INI1 SMARCA4 EZH2 EZH2 activity down-regulated SWI/SNF PRC2 INI1 SMARCA4 PRC2 target genes PRC2 target genes Stem cell programs Stem cell programs Self-renewal and Block in differentiation Adapted from Wilson 2010 Quiescence and Differentiation 19 INI1 Loss Creates an Oncogenic Dependency on EZH2 in Tumors Stem or Progenitor Cells Highly dependent on SWI/SNF EZH2 activity INI1 EZH2 knockout reverses oncogenesis induced by INI1 loss PRC2 EZH2 INI1fl/fl CD4-Cre (n=8) INI1fl/fl EZH2fl/fl CD4-Cre (n=23) SMARCA4 PRC2 target genes Hyper-repression of PRC2 targets Antitumor Activity in Xenograft Model of INI1-negative MRT (G401) Potentiation Stem cell programs of stem cell programs Oncogenic Transformation Adapted from Wilson 2010 20 Oncogenic chromatin readers BET Family NUT midline carcinoma (NMC) is an aggressive form of squamous cell cancer overall survival of just 6.7 months (French, 2014). This disease is characterized by translocations of the NUT gene, which typically fuse NUT to one of two bromodomain and extra terminal (BET) family genes, BRD4 or BRD3. Together BET FAMILY BET family proteins Acetyl-lysine readers that promote transcription by interacting with and recruiting the positive transcription elongation factor (pTEFb) and Mediator complexes to chromatin BRD-NUT megadomains promote the expression of genes that drive NMyC pathogenesis. Conclusion Role driver dans la survenue de cancer Molécules en cours de développement
