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DNA Methylation “Epigenetica en Biomedicina: Del Conocimiento al Desarrollo Biotecnológico y Farmacéutico” Dr. Manel Esteller [email protected] Director Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL) ICREA Research Professor Professor of Genetics, University of Barcelona WE ARE MORE THAN OUR GENES ! DOLLY inrecentyearsepigeneticalterationshavecometopr ominenceincancerresearchinparticularhypermethy lationofcpgislandslocatedinthepromoterregionso ftumorsuppressorgenesisnowfirmlyestablishedasa nimportantmechanismforgeneinactivationincancer oneofthemostremarkableachievementsinthefieldha sbeentheidentificationofthemethylcpgbindingdom ainfamilyofproteinswhichprovidemechanisticlink sbetweenspecificpatternsofdnamethylationandhis tonemodificationsalthoughmanyofthecurrentdatai ndicatethatmethylcpgbindingproteinsplayakeyrol einmaintainingatranscriptionallyinactivestateo fmethylatedgenesmbd4isalsoknowntobeinvolvedine xcisionrepairoftgmismatchesthelatterisamembero fthisfamilyofproteinsandappearstoplayaroleinre ducingmutationsat5methylcytosinethisreviewexam inesthecontributionofmethylcpgbindingproteinsi ntheepigeneticpathwayofcancer The Epigenetic Dice: -DNA Methylation -Histone Modifications -ncRNAs -…. Cover by Sanchez-Mut and Esteller, Dev Cell, November 15th 2010 Epigenetics Parameters Nature, 429, 457-63, 2004 Imprint of famine seen in genes of Second World War babies 60 years on Towards the Human Epigenome A B 2,00 2,00 2,00 1,60 1,60 1,60 1,20 1,20 1,20 0,80 0,80 0,80 ESD 5mC ESD Ac H4 ESD Ac H3 0,40 0,40 0,40 0,00 0,00 0,00 0 15 30 45 60 75 0 15 30 45 60 75 0 15 30 45 60 75 Age (years) Age (years) Age (years) C D 50-year-old 3-year-old twins 50-year-old twins Francis Collins, director of the National Human Genome Research Institute, said: "Here's something where Mendel, Watson and Crick all seem to have missed some crucial goodies" Discordant Twins for Breast Cancer Heyn et al., Carcinogenesis 2012 Lupus eritematoso sistémico Autoimmune disease affecting many tissues and organs Autoantibodies against nuclear antigens, specially against DNA, histones and nucleosomes Epigenetics, Discordant Twins and Disease Diabetes Type 2, Target tissue: Fat Twin A Twin methylation % methylation Twin A methylation % % 20-yo TD2-twins (397-398) TD2-twins (529-530) twins % methylation Twin B Systemic Lupus Erythematosus, Target tissue: Lymphocytes 082_01 AVG_Beta vs 082_02 AVG_Beta 030_01 AVG_Beta vs 030_02 AVG_Beta 061_01 AVG_Beta vs 061_02 AVG_Beta 1 1 1 0.80 0.80 0.80 a a a t t t e e e B 0.60 B 0.60 B 0.60 _ _ _ G G G V V V A A A 1 1 1 0 0 0 _ 0.40 _ _ 2 0.40 0.40 0 1 8 3 6 0 0 0 Average SLE Twin SLE Average 0.20 Average SLE Twin SLE Average 0.20 Twin SLE Average 0.20 0 0 0 0 0.20 0.40 0.60 0.80 1 082_02 AVG_Beta 0 0.20 0.40 0.60 0.80 1 0 0.20 0.40 0.60 0.80 1 Average Healthy Twin 030_02 AVG_Beta 061_02 AVG_Beta Average Healthy Twin Average Healthy Twin DNA methylation contributes to natural human variation au 100 A African-American (AF) B 100 100 Caucasian-American (CA) 99 Han Chinese-American (AS) Height 40 60 80 100 120 100 80 60 40 C AF AS CA PCA1 1 0 1 2 1 1 0 - 2 2 - -2 -1 0 1 2 PCA2 AF CA AS D Ancestral allele allele (%) Ancestral 0 20 40 60 80 100 80 60 40 20 0 Heyn et al., Genome Research 2013 DNA methylation and natural human variation: pathways and diseases DNA methylation and natural human variation: pathways and diseases Taste Skin Pigmentation DNA methylation and natural human variation: pathways and diseases Taste Skin Pigmentation Diabetes Infection (HBV, HIV, Measles Parkinson’s Virus, E. coli) DNA methylation plasticity of human adipose-derived stem cells in lineage commitment A OSTEOGENIC MYOGENIC PTPRS - 293 + 92 Differentiation Suppression of Differentiation Suppression of medium the inductor medium the inductor Adult Stem Cells_1 Adult Stem Cells_2 In vitro myocytes_1 PTPRS B - 293 + 92 C In vitro 800 myocytes_2 600 ) expression 400 SAA1 - 159 + 162 Cells 200 myocytes PTPRS vs GAPDH) vsPTPRS Relative ( tem S Regressed 0 1 2 3 from ( Adult Stem Cells_1 SAA1 Adult - 159 + 162 Stem Cells_2 ) 150 In vitro Osteocytes_1 Cells 100 expression osteocytes In vitro tem S Osteocytes_2 Regressed 50 from ( SAA1 vs GAPDH)vsSAA1 ( Relative 0 1 2 3 PIWIL2 PIWIL2 - 152 + 160 - 152 + 160 ) Adult 150 Stem Cells_1 Cells 100 osteocytes Adult tem S Stem Cells_2 Regressed expression from 50 ( ) PIWIL2 vs GAPDH) vs PIWIL2 Relative In vitro ( myocytes_1 0 1 2 3 4 5 Cells In vitro myocytes osteocytes_2 tem S Regressed from ( Berdasco et al., American Journal of Pathology 2012 Stem Cells and Sirtuins Blue: DAPI Green: alpha-actin Embryonic Stem Cells (H-181) Differentiation upon siRNA of SIRT1 (mesodem) Differentiation upon Sirtinol treatment (24h) Differentiation upon bFGF withdrawal Epigenetic Marks The Epigenetic Marks: DNA Methylation Esteller, Nat Rev Genet 2007 Esteller, New England Journal of Medicine, 2008 Heyn and Esteller, Nature Review Genetics, 2012 Roriguez-Paredes and Esteller, Nature Medicine, 2011 THE HISTONE CODE H3, N-terminus H4, N-terminus Me Ac P Ac Me Ac Ac Ac Ac activation 4 9 10 14 18 23 27 36 5 8 12 16 20 ARTKQTARKSTGGKAPRKQLATKAARKSAPATGGVKKPH- SGRGKGGKGLGKGGAKRHRKVLRDN- Me Ac silencing The Dark Genome Melo and Esteller, FEBS Letters, 2010 Melo and Esteller, FEBS Letters, 2010 Nature Genetics, 2009 Cancer Cell, 2010 Science, 2009 Esteller, Nature Reviews Genetics 2011 Rodriguez-Paredes and Esteller, Nature Medicine, 2011 Preclinical Clinical Epigenetic drugs stage stage DNA Demethylating Agents Histone Deacetylase Inhibitors Histone Methyltransferase Inhibitors Histone Demethylase Inhibitors Histone Kinase Inhibitors Histone Acetyltransferase Inhibitors Bromodomain Inhibitors Sirtuin Inhibitors microRNA Related Compounds Rodriguez-Paredes and Esteller, Cancer Discovery 2011 Outside Cancer Rett Syndrome Rett Syndrome (RS) is a neurodevelopmental disorder believed to affect 1 in 10,000 females.. Germline mutations in MECP2 (Methyl-CpG Binding Protein-2) found in 65% of Rett patients. MECP2 is located in Xq28. Girls with Rett Syndrome appear to develop normally until 6 to 18 months of age. They then enter a period of regression, losing speech and hand skills they had acquired. Most girls develop seizures, repetitive hand movements, irregular breathing and motor-control problems. A slowing of the rate of head growth also becomes apparent. Most researchers agree that RS is a developmental disorder rather than a progressive, degenerative disorder. The girls can live to adulthood, but most never regain the ability to use their hands or to speak. Clustering expression analysis and release of MeCP2- Silencing in Rett Syndrome Patients R294X R106W NoMut2 R255X NoMut4 NoMut1 NoMut3 P391X T158M R306C MPP1 MeCP2 NAB I UB B UB B Control R106W - 264 + 103 N1 N2 Gene Primer sequence Annealing MPP1 Forward 5´-YGAATTTGGTTAGGGTATTYGGG-3´ 57 ºC Reverse 5´-CTTAAAAATCATCTCRCAAAAACT-3´ N2 MPP1 125 123 126 112 125 120 56 53 77 71 36 38 35 49 36 41 105 108 84 90 Human Mutation, 2005 Mouse Model of Rett 1 3 2 7.5gr/10.25cms 1.-Encéfalo 299mg 2.-Mesencéfalo 3.-Cerebelo 1 3 2 8.1gr/11.05cms 310mg Dynamic DNA Methylation Reconfiguration During Brain Development Lister et al., Science 2013 •DNA Methylation and Schizophrenia DNA Methylation Map of Mouse Brain Identifies Targets of Epigenetic Disruption in Alzheimer’s Disease Sanchez-Mut et al., Brain 2013 Promoter hypermethylation of the phosphatase DUSP22 mediates PKA-dependent TAU phosphorylation and CREB activation in Alzheimer's disease Sanchez-Mut et al., Hippocampus 2013 DNA Methylation Profiling of Human Atheroesclerosis Zaina et al., Circulation: Cardiovascular Genetics 2014 …Epigenomes “The Book of Life” (Almost…) Figure 1 Esteller Epigenetic differences in monozygotic twins and distinct penetrance of disease Epigenetic differences among species and distinct skills Epigenetic differences among species and distinct skills Epigenetic differences in cloned animals and distinct phenotypes Epigenetic Epigenetic changes in changes development in germinal and growth cells Epigenetic alterations and human diseases Esteller, The Lancet, 2008 Heyn and Esteller, Nature Reviews Genetics, 2012 Heyn and Esteller, Nature Reviews Genetics, 2012 A 450,000 CpG Site Prognostic Classifier of 500 Non-Small Cell Lung Cancer Patients A. B. Group 1 Group 2 Adeno Squamous Large 0 0.5 1 1.0 Hazard ratio, 2.30 (95% CI, 1.36-3.89) p: 0.002 0.8 free free survial - 0.6 group2 (n=174) 0.4 0.2 group1 (n=24) 0 Proportion with recurrence with Proportion 0 5 10 15 20 Years after surgery C. Group 1 Group 2 D. Adeno Squamous Large 0 0.5 1 1.0 Hazard ratio, 2.46 (95% CI, 1.32-4.59) p: 0.005 0.8 free free survial - 0.6 group2 (n=114) 0.4 0.2 group1 (n=33) 0 Proportion with recurrence with Proportion 0 5 10 15 20 Years after surgery Cancer of Unknown Primary The Distinct DNA Methylomes of Newborns and Centenarians 16,800,000 82% 1.0 Distance correlation to closest CpG site 80% 16,600,000 78% 76% 16,400,000 74% level (%) level 16,200,000 72% CpG methylation CpG methylation 70% Methylated Methylated CpG sites 16,000,000 68% NB Y26 Y103 NB Y26 Y103 Correlation 0.8 0.1 1 10 100 1000 0.6 Distance Chromosome 2 1.00 0.9 ** Meth. level Meth. ** 0.90 ** ** 0.8 0.4 0.80 0.7 0.70 0.6 0.8 0.60 ** 0.5 0.50 NB NB 0.40 0.4 Y103 ** Y103 0.30 0.3 0.6 0.20 0.2 Mean methylation level methylation Mean 0.10 level methylation Mean 0.1 Chromosome 8 0.00 0 Meth. level Meth. 0.4 Promoter Exonic Intronic Intergenic CG poor CGI promoters promoters CpG poor CpG island promoters promoters 140; 17% 479; 45% 9000 8000 DMRs 7000 15669; Hypomethylated 6000 87% in Y103 671; 83% 585; 55% Hypermethylated 5000 in Y103 4000 Tissue-specific genes Housekeeping genes 3000 8; 13% DMR numberDMR 2000 611; 34% 1000 0 2261; 13% Promoter Exonic Intronic Intergenic 1200; 66% 56; 87% Proc Natl Acad Sci USA, 2012 Diseases Associated with Premature Aging: Hutchinson-Gilford Progeria and Werner syndrome HG/W Nonagenarians Newborn Prediction of Biological Age Using DNA Methylation The Biomedical Iceberg The Genome The Epigenome [email protected] Manel Esteller, 2014 .
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