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Dr. Manel Esteller Epigenetics and Rett Syndrome

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Dr. Manel Esteller Epigenetics and Rett Syndrome Epigenetics and Rett Syndrome Dr. Manel Esteller Director Elect Josep Carreras Institute (IJC) Director Cancer Epigenetics and Biology Program (PEBC) Bellvitge Biomedical Research Institute (IDIBELL) Genetics Professor, University of Barcelona ICREA Research Professor [email protected] Urdinguio, Sanchez-Mut and Esteller, Lancet Neurology, 2009 miRNA PROCESSING Genetic syndromes caused by mutations in Epigenetic genes FMRP Fragile X Syndrome DNA METHYLATION DGCR8 DiGeorge Syndrome Goiter multinodular 1 Syndrome Amyotrophic lateral sclerosis (ALS) TARDBP DNA METHYLATION DICERDICER miRNA/mRNA XPO5 DNMT1 Hereditary Sensory and Autonomic Drosha Pri-mRNA Neuropathy 1 (HSAN1) RISC DNMT3 Immunodeficiency-Centromeric Instability-Facilal Anomalies (ICF1) miRNA Pre-mRNA MeCP2 Rett Syndrome Angelman Syndrome CH3 HISTONE MODIFICATIONSHISTONEHISTONE MODIFICATIONS MODIFICATIONS Claes- Jensen X-linked Mental Retardation Syndrome JARIDC1JARIDC1 MLL2 Kabuki Syndrome 1 Siderius X-linked Mental Retardation Syndrome PHF8PHF8 MLL2 EZH2EZH2 Weaver Syndrome 2 Kabuki Syndrome JMJD3JMJD3 EHMT1EHMT1 KleefstraSyndrome Sotos Syndrome Weaver Syndrome 1 NSD1NSD1 CREBBP/CREBBP/ Rubinstein-Taybi Syndrome Beckwith-Wiedemann Syndrome P300P300 Berdasco and Esteller, Hum Genet. 2013 H4 H4 Brachydactyl- mental retardation Syndrome HDAC4HDAC4 MYST4MYST4 Genitopatellar Syndrome Say-Barber-Biesecker-Young-Sympson (SBBYS) - N--Nterminal- terminal …K……K… DRLVKRHRKAGGKGLGKGGKGRGS DRLVKRHRKAGGKGLGKGGKGRGS 1 1 3 3 5 5 8 8 1212 1616 1818AcAc2020 9191AcAc CHROMATINPP MeMeAcAc AcAc MeMe- REMODELINGAcAc PP MeMe FACTORS ERCC6ERCC6 Alpha-Thalassemia X-linked mental retardation Syndrome Cockayne Syndrome, type A ATRXATRX Mental Retardation-hypotonic facies Syndrome, X-linked Cockayne Syndrome, type B ERCC8ERCC8 CDH7CDH7 CHARGE Syndrome Coffin- Siris Syndrome ARID1BARID1B SMARCB1SMARCB1 Coffin- Siris Syndrome Coffin- Siris Syndrome ARID1AARID1A SMARCAA4SMARCAA4 Coffin- Siris Syndrome Floating- Harbor Syndrome SRCAPSRCAP Coffin- Siris Syndrome SMARCA2SMARCA2 Nicolaides-Baraitser Syndrome Spinocerebellar ataxia 7 ATXN7ATXN7 CHROMATINCHROMATIN-REMODELING-REMODELING FACTORS FACTORS Rett Syndrome Rett Syndrome (RS) is a neurodevelopmental disorder believed to 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. 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. MeCP2 ➢ Protein with affinity for methylated DNA (CpG pairs). ➢ i.e. Fraga et al. NAR 2003; Ballestar et al. EMBO J 2003 ➢ Transcriptional repressor. ➢ i.e. Fournier et al. EMBO J 2002; Ballestar et al. EMBO J 2003; Lopez-Serra et al. Cancer Res 2006; Lopez-Serra et al., Oncogene 2008 Two main functional domains: MBD TRD Lopez-Serra et al., British Journal of Cancer 2008 Establishment of Immortalized Lymphocyte Cell Lines Healthy Donor MeCP2 Rett Patient Lymphoblastoid Cell Lines Available MeCP2 CDKL5 NTG1 FOXG1 n=23 n=7 n=3 n=2 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 Ballestar et al., 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 Looking for transcriptional changes Wild type mice Mecp2-null mice Cortex Cortex Midbrain Midbrain Cerebellum Cerebellum RNA Extraction RNA Extraction Amplification Amplification Candidate overexpressed genes Reverse Reverse in Mecp2-null mice transcription and transcription and labeling labeling Hybridization Image scanning Data analysis Mobp Dlk1 – Gtl2 Myelin-associated oligodendrocytic basic protein Family of abundant CNS myelin proteins Localizes to major dense line of compact myelin Plagl1 Ddc zinc finger protein regulator of apoptosis DOPA decarboxylase and cell cycle arrest (Zac1) L-Dopa Dopamine L-5-HTP Serotonine Urdinguio et al., PLoS ONE, 2008 Effective drugs for Parkinson's reduce symptoms of Rett syndrome in mice 100 8 vehicle 80 L-Dopa L-Dopa / Ddci 6 60 * 4 * * 40 Percent survival 2 20 ** *** Total ScoreSymptom 0 0 60 70 80 90 100 6 7 8 9 10 Life span (days) Time (weeks) *** *** * ** *** *** ** *** *** *** *** ** 1.0 * ** 1.0 * * 1.0 * * * * * *** * ** ** * *** 0.5 0.5 0.5 Tremor Mobility Breathing 0.0 0.0 0.0 7 w eeks 8 w eeks 9 w eeks 10 w eeks 7 w eeks 8 w eeks 9 w eeks 10 w eeks 7 w eeks 8 w eeks 9 w eeks 10 w eeks Szczesna et al., Neuropsychopharmacology 2014 An Impact of MeCP2 Disruption on lncRNA Transcription: The Mouse Model of Rett Syndrome Wild type MeCP2 KO Wild-type MeCP2 KO Brain Brain Mouse LncRNA Microarray GAMMA-AMINOBUTYRIC ACID RECEPTOR, RHO-2 AK08122 7 AK081227/RPL 5 38** Gabrr2/RPL38 W… 2,0 K… 4 W… 3 K… * 1,0 * 2 * * 1 0,0 0 BO FC HIP HTA TH C Petazzi et al., RNA Biology, 2013 MECP2 duplication syndrome Intellectual disability, weak muscle tone in infancy, feeding difficulties, poor or absent speech, seizures, delayed development of motor skills, such as sitting, loss of previously acquired skills (developmental regression), one third cannot walk without assistance. An Increase in MECP2 Dosage Impairs Neural Tube Formation •We report a new in vivo model of MeCP2 overexpression. •The increase in MeCP2 dosage prevents the correct formation of the neural tube. •MeCP2-electroporated cells show an ectopic neuronal localization. •Neuroblasts overexpressing MeCP2 undergo decreased proliferation and increased death. Petazzi et al., Neurobiology of Disease, 2014 Circadian Cycle-Dependent MeCP2 and Brain Chromatin Changes Martínez de Paz et al, PLoS One (2015) Genomics Girls with Clinical Features of Rett Syndrome but without any mutation in the “usual suspect” genes Whole-Exome Sequencing Mutations in JMJD1C (jumonji domain containing 1C) are involved in Rett syndrome and intellectual disability Saez et al., Genetics in Medicine , 2015 Other Mutations in Histone Modifiers Are Also Involved in Intellectual Disability Dravet syndrome Pitt-Hopkins syndrome SCN1A mutation TCF4 mutation Lucariello et al., Human Genetics 135, 1343-1354, 2016 Final Update Mllt2h Eya2 Suggested transcriptional factor Transcriptional coactivator Specifically expressed in Purkinje cell (Af4) Expressed during development of several organs S100a9 S100 calcium binding protein A9 (calgranulin B) IRAK1 !!!! Marenholz I, Heizmann CW and Fritz G. (2004) Biochem Biophys Res Commun. 322:1111-22 Urdinguio et al., PLoS ONE, 2008 Inhibition of Gsk3b reduces NFk-B signaling and rescues synaptic activity to improve the Rett syndrome phenotype in Mecp2-knockout mice Jorge-Torres et al., Cell Reports 2018 Treatment with a GSK3β inhibitor (SB216763) Improves Neuronal Functionality WT KO VEH KO+SB216763 Merge Psd95 Dapi WT Map2 KO VEH KO KO + + KO Thresholding SB216763 Branching Postsynaptic Jorge-Torres et al., Cell Reports 2018 Future Genetic Edition of MeCP2 in Neurons Normal Neurons Neurons with MeCP2 Loss Genetic Edition of MeCP2 in Neurons MECP2DAPITUJ Obtaining GABAergic Neurons CTR Protocol GABADAPITUJ Thanks to all the families and research supporters…. Sonia Guil Raul Delgado-Morales Catalan Rett Syndrome Association Valencian Rett Syndrome Association.
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