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Gene Silencing

Gene Silencing. Arlés Urrutia Biomedicine and Biotechnology Institute . Autonomous University of Barcelona. (IBB-UAB) Neurochemistry Lab . How do the many cell types of the body maintain drastically different gene expression patterns while sharing exactly the same DNA?. Evolutionary

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Gene Silencing

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  1. Gene Silencing Arlés Urrutia Biomedicine and BiotechnologyInstitute. AutonomousUniversity of Barcelona. (IBB-UAB) NeurochemistryLab.

  2. How do the many cell types of the body maintain drastically different gene expression patterns while sharing exactly the same DNA? Evolutionary SNP´s – CNV´s Protein Expression BiochemicalActivity

  3. CONTENT • DNA methylation • Methyl-CpG-bindingproteins: MeCP2. • De novomethyltransferase: Dnmt1. • mSinA3 – HDAC Complex. • HistoneModification. • Acetilation & Methylation • ChromatinImmunoprecipitationAssay • Inheritance & Life Time • Diseases & Therapies

  4. DNA METHYLATION Schematic diagram of the molecular mechanism of methylase inheritance and transcriptional repression. HDAC1/2-mSin3A-MeCP2 Complex organized chromatin integrity. (Kimura, 2003)

  5. HISTONE MODIFICATION Carpenter(Abcam), 2005 Recruitment of ProteinstoHistones. B. Proteinsfoundthatassociatedpreferentiallywithmodifiedversions of histones H3 and histone H4. (Kouzarides, 2007)

  6. HISTONE MODIFICATION

  7. HISTONE MODIFICATION HAT HDAC HISTONE CODE Slide courtesy of Trevor Archer adapted from Jenuwein & Allis, Science 2001

  8. 15 February 2001

  9. CHROMATIN IMMUNOPRECIPITATION ASSAY

  10. INHERITANCE & LIFE TIME Chromosome 15 (q11-13) are deleted or unexpressed  MOTHER FATHER Prade-WilliSyndrome Maternal AlleleSilenced. Cognitive, Breathing and feedingdificulties. AngelmanSyndrome. neuro-geneticdisorder Happydemanor

  11. INHERITANCE & LIFE TIME Mapping chromosomal regions with differential DNA methylation in MZ twins by using comparative genomic hybridization for methylated DNA. Presence of green and red signals that indicate hypermethylation and hypomethylation events, whereas the 3-year-old twins have a very similar distribution of DNA methylation indicated by the presence of the yellow color. Fraga et al, 2005

  12. DISEASES Epigenetictherapywith DNA methylationinhibitors (DNMTi) and HDAC inhibitors (HDACi). Combinationtherapies are likelytogaintraction in thefuture because of theinherentself – reinforcingnature of silencingmechanisms. Futurebreakthroughscould come fromthe use toepigeneticdrugstoactivatemiRNAsor use of drugsto target cancerstemcellsafter tumor debulkingby estándar chemotherapy. (Jones & Baylin, 2007)

  13. Changingtheview of whatInheritanceis. INHERITANCE & LIFE TIME • Ourparentslifeisaffectingusdirectly, duringtheeggs and embriodevelopments. Do the genes havememory? • 30.000 genes isnotenoughforthisammount of differencesbetweenindividuals, evenidenticaltwins. • Theapereance of Beckwith-Wiedemannsyndrome, (BWS)is 3/65 by In Vitro Fertilization in Victoria, AU. Couldthisproceduretriggerepigeneticsswitchesfordisseased? • Istheimprintinganadaptationfromtheparentstothenextgeneration? TheOverkalix case, in Sweden (foodavailability and longevity).

  14. TheExperts SpainResearch . CNIO.

  15. REFERENCES • Williamson S. Christodoulou, J. (2006) RettSyndrome: new clinical and molecular insights. Eur J HumGenet. 14, 896-903. • Fuks, F. (2005) DNA methylation and histonemodifications: teaming up tosilence genes. CurrOpi in Genet & Develop. 15:1-6. • Kimura, H. Shiota, K. (2003) Methyl-CpG-bindingprotein, MeCP2, is target MoleculeforMaintenance DNA Methyltransferase, Dnmt1. J.Biol. Chem. 278:4806 – 4812. • Robertson, K. (2005) DNA methylation and humandisease. NatureReviews,Genetics. 6:597. • Jones, P. Baylin, S. (2007) TheEpigenomics of Cancer. Cell. 128:683-692. • Nan, X. Ng, HH. Johnson, C. Laherty, C. Turner, B. Eisenman, R. Bird, A. (1998) Transcriptionalrepressionbymethyl-CpG-bindingprotein MeCP2 involves a histonedeacetylasecomplex. NatureLetters. 393:386-389. • Cullum, R. Alder, O. Hoodless, P. (2011) TheNextgeneration: Using new sequencingtechnologiestoanalyse gene regulation. Respirology. 16:210-222.

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