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Genetic, Epigenetic and Transcriptome Studies of Tourette Syndrome and Tic Disorders

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GENETIC, EPIGENETIC AND TRANSCRIPTOME STUDIES OF TOURETTE SYNDROME AND TIC DISORDERS PhD thesis LUCA PAGLIAROLI Doctoral School of Molecular Medicine Semmelweis University Supervisor: Csaba Barta, MD, PhD Official reviewers: Xénia Gonda, MD, PhD Bálint László Bálint, MD, PhD Head of the Final Examination Committee: Illona Kovalszky, MD, PhD, DSc Members of the Final Examination Committee: Beáta Tör őcsik, PhD Zoltán Gáspári, PhD Budapest 2019 INDEX 1. ABBREVIATIONS - 5 - 2. INTRODUCTION - 11 - 2.1 Tourette Syndrome - 11 - 2.1.1 TS Diagnosis - 12 - 2.1.2 Definition of tics - 12 - 2.1.3 The Cortico-Striato-Thalamo-Cortical Circuit - 13 - 2.1.4 The hidden heritability of TS - 14 - 2.2 Genetic background of Tourette Syndrome - 15 - 2.2.1 CNVs and Tourette Syndrome - 15 - 2.2.2 VNTRs and Tourette Syndrome - 17 - 2.2.3 SNPs and Tourette Syndrome - 18 - 2.2.3.1 Strong Positive Findings - 19 - 2.2.3.2 Single Positive Findings - 21 - 2.2.3.2.1 Glutamate - 21 - 2.2.3.2.2 Oxidative Stress - 22 - 2.2.3.2.3 Dopamine & Serotonin - 22 - 2.2.4 Disentangling the Genetic Complexity of Tourette Syndrome - 23 - 2.3 Epigenetic Background of Tourette - 24 - 2.3.1 The role of DNA Methylation in epigenetic regulation - 25 - 2.3.1.1 DNA Methylation and Tourette Syndrome - 27 - 2.3.2 The role of microRNAs in the regulation of gene expression - 27 - 2.3.2.1 MicroRNAs and Tourette Syndrome - 30 - 2.3.3 Increased Effort to Study Methylation and Tourette Syndrome - 30 - 2.4 Animal Models - 31 - 2.4.1 Abnormal Involuntary Movements (AIMs) - 31 - 2.4.2 Translating AIMs in Tourette Syndrome - 32 - 2.5 TS-EUROTRAIN Network - 33 - 2.5.1 TS-EUROTRAIN Tasks - 33 - 3. OBJECTIVES - 35 - - 1 - 4. METHODS - 36 - 4.1 Genetic studies of Tourette Syndrome - 36 - 4.1.1 In silico work - 36 - 4.1.2 Samples - 37 - 4.1.3 Genotyping - 38 - 4.1.4 Statistical Analysis - 38 - 4.1.5 Real-Time PCR - 39 - 4.2 Epigenetics studies of Tourette Syndrome - 40 - 4.2.1 Samples - 40 - 4.2.2 Infinium HumanMethylation450 Bead Chip Kit (Illumina 450K) - 40 - 4.2.3 Statistical Analysis - 40 - 4.2.4 Enrichment of Gene Ontology terms - 40 - 4.3 Animal model exhibiting abnormal involuntary movements (AIMs) - 41 - 4.3.1 Stereotaxic surgery - 41 - 4.3.2 Animal treatment - 42 - 4.3.3 Phenotype scoring - 42 - 4.3.4 Samples extraction - 42 - 4.3.5 RNA sequencing and data analysis - 42 - 4.3.6 qPCR validation of selected CREB1 targets - 43 - 4.3.7 Reduced Representation Bisulfite Sequencing (RRBS) - 44 - 4.3.8 RRBS protocol - 44 - 4.3.9 RRBS data analysis - 45 - 5. RESULTS - 47 - 5.1 Genetic studies of Tourette Syndrome - 47 - 5.1.1 Genetic variation identified by meta-analysis - 47 - 5.1.2 Over-transmission of alleles in TS patients - 47 - 5.1.3 Results of the other genetic variations analyzed 50 5.2 Epigenetic studies of Tourette Syndrome 52 5.2.1 DNA methylation profile in the blood of TS patients: an EWAS study 52 5.2.2 Enrichment analysis of the annotated CpGs 57 - 2 - 5.3 Abnormal Involuntary Movements (AIMs) animal model 59 5.3.1 Striatal DA Determination 62 5.3.2 The Triggering of the Phenotype by L-DOPA and Riluzole 62 5.3.3 Analysis of the Transcriptome 63 5.3.3.1 Differentially expressed genes: the mRNA is talking 63 5.3.3.2 Identification of the Top Upstream Regulators 64 5.3.3.3 CREB1 target genes 66 5.3.3.4 Revealing the molecular mechanism of Riluzole 69 5.3.3.5 Validation of the mRNA data 76 5.3.4 DNA methylation profile in the striatum of our AIMs model 77 5.3.4.1 Distribution of CpGs in the rat genome 77 5.3.4.2 Identification and localization of the methylated sites 79 5.3.4.3 A new way of analysis: merging the lesion and contralateral side 81 5.3.4.4 Genes with marked changes in methylation 83 5.3.4.5 The biological relevance of the DMSs 85 6. DISCUSSION 86 6.1 Genetic studies of Tourette Syndrome 86 6.2 Epigenetic studies of Tourette Syndrome 88 6.3 Abnormal Involuntary Movements (AIMs) animal model 90 7. CONCLUSION 97 7.1 Genetic studies of Tourette Syndrome 97 7.2 Epigenetic studies of Tourette Syndrome 97 7.3 Abnormal Involuntary Movements (AIMs) animal model 98 8. SUMMARY 99 9. ÖSSZEFOGLALÁS 100 10. PHD CANDIDATE’S PUBLICATIONS 101 10.1 Publications discussed in the PhD dissertation 101 10.2 Publications not discussed in the PhD dissertation 102 - 3 - 11. REFERENCES 104 12. ACKNOWLEDGMENT 134 - 4 - 1. ABBREVIATIONS 3′UTR: 3 ′ Untranslated Region 5-hmC: 5-hydroxymethyl-cytosine 6-OHDA: 6-hydroxydopamine AADAC: Arylacetamide deacetylase ACP1: Acid phosphatase 1, soluble ADAM1: ADAM metallopeptidase domain 1A (pseudogene) ADHD: Attention Deficit Hyperactivity Disorder ADORA1: Adenosine A1 receptor ADORA2A: Adenosine A2a receptor AIM: Abnormal Involuntary Movement ARC: Activity regulated cytoskeleton associated protein ATF3: Activating transcription factor 3 BAG3: BCL2 associated athanogene 3 BLM: BLM RecQ like helicase Bp: Base Pair BRD1: Bromodomain containing 1 BRPF3: Bromodomain and PHD finger containing 3 BTBD9: BTB (POZ) domain containing 9 CCND3: Cyclin D3 CDC37: Cell division cycle 37 CDH13: Cadherin 13 CDH2: Cadherin 2, type 1, N-cadherin neuronal CDK19: Cyclin dependent kinase 19 CDKN1A: Cyclin dependent kinase inhibitor 1A CHAT: Choline acetyltransferase CHRNA7: Cholinergic receptor, nicotinic, alpha 7 (neuronal) CLINT1: Clathrin interactor 1 CNR1: Cannabinoid receptor 1 CNTN6: Contactin-6 CNTNAP2: Contactin associated protein-like 2 - 5 - CNV: Copy Number Variation COL27A1: Collagen, type XXVII, alpha 1 COL8A1: Collagen, type VIII, alpha 1 COMMD1: COMM domain-containing protein 1 COMT: Catechol-O-methyltransferase CpG: Cytosine-Phosphate-Guanine dinucleotide CREB1: cAMP-responsive element binding protein 1 CREM: cAMP responsive element modulator CRH: Corticotropin releasing hormone CSRNP1: Cysteine and serine rich nuclear protein 1 CSTC: Cortico-Striato-Thalamo-Cortical DA: Dopamine DMS: Differentially Methylated Site: DNMTs: DNA Methyltransferases DPP6: Dipeptidyl-peptidase 6 DRD1: Dopamine receptor D1 DRD2: Dopamine receptor D2 DRD4: Dopamine receptor D4 DSM-5: Diagnostic and Statistical Manual of Mental Disorders DUSP14: Dual specificity phosphatase 14 EGR4: Early growth response 4 EHD4: EH domain containing 4 ESR: Early Stage Researcher EWAS: Epigenome-Wide Association Study FGF13: Fibroblast growth factor 13 FOS: Fos proto-oncogene, AP-1 transcription factor subunit FOSB: FosB proto-oncogene, AP-1 transcription factor subunit FRMD6: FERM domain containing 6 GAA: Glucosidase alpha, acid GABBR1: Gamma-aminobutyric acid type B receptor subunit 1 GADD45B: Growth arrest and DNA damage inducible beta GADD45G: Growth arrest and DNA damage inducible gamma - 6 - GDNF: Glial cell Derived Neurotrophic Factor GGRI: GWAS Replication Initiative Gpe: Globus Pallidus Externus Gpi: Globus Pallidus Internus GPR3: G protein-coupled receptor 3 GRIK3: Glutamate ionotropic receptor kainate type subunit 3 GRIK4: Glutamate ionotropic receptor kainate type subunit 4 GRIN2B: Glutamate ionotropic receptor NMDA type subunit 2B GRM4: Glutamate metabotropic receptor 4 GRM8: Glutamate metabotropic receptor 8 GSTP1: Glutathione s-transferase pi 1 GWAS: Genome Wide Association Study HDC: Histidine decarboxylase hEAE6: Homolog of Esa1-associated factor 6 HIST1H4E: Histone cluster 1 H4 family member e HPLC-ECD: Electrochemical detection technique coupled with high-performance liquid chromatography HSPA5: Heat shock protein family A (Hsp70) member 5 HTR2A: 5-hydroxytryptamine Receptor 2A ID1: Inhibitor of DNA binding 1, HLH protein IGSF9B: Immunoglobulin superfamily member 9B Illumina 450K: Infinium HumanMethylation450 Bead Chip Kit ILR1N: Interleukin 1 receptor antagonist IMMP2L: Inner mitochondrial membrane peptidase subunit 2 ING5: Inhibitor of growth 5 INHBA: Inhibin beta A subunit IRS2: Insulin receptor substrate 2 JUN: Jun proto-oncogene, AP-1 transcription factor subunit JUNB: JunB proto-oncogene, AP-1 transcription factor subunit KCNK9: Potassium channel two pore domain subfamily K member 9 KLF4: Kruppel like factor 4 LHX6: LIM homeobox 6 - 7 - LMO1: LIM domain only 1 MAOA: Monoamine oxidase A MCPerm: Monte Carlo Permutation MECP2: Methyl-CpG-binding protein 2 MEIS1: Meis homeobox 1 MIDN: Midnolin MORN4: MORN repeat containing 4 NDUFV1: NADH ubiquinone oxidoreductase core subunit V1 NFIL3: Nuclear factor, interleukin 3 regulated NPAS4: Neuronal PAS domain protein 4 NPTX2: Neuronal pentraxin 2 NPY: Neuropeptide Y NR4A1: Nuclear receptor subfamily 4 group A member 1 NR4A3: Nuclear receptor subfamily 4 group A member 3 NRGN: Neurogranin NRXN1: Neurexin 1 NTN4: Netrin 4 OCD: Obsessive-Compulsive Disorder OLFM1: Olfactomedin1 OR: Odds Ratio Ov.T: Over-Transmitted P: P-value PANDAS: Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection PARP1: Poly (ADP-ribose) polymerase 1 PD: Parkinson’s disease PDE10A: Phosphodiesterase 10A PDXK: Pyridoxal kinase PDYN: Prodynorphin PER1: Period circadian clock 1 PIGX: Phosphatidylinositol glycan anchor biosynthesis class X PIM3: Pim-3 proto-oncogene, serine/threonine kinase - 8 - PLAT: Plasminogen activator, tissue type PLEKHG3: Pleckstrin homology and RhoGEF domain containing G3 PTGS2: Prostaglandin-endoperoxide synthase 2 PVR: Poliovirus receptor RELN: Reelin RELN REM2: RRAD and GEM like GTPase 2 RHEB: Ras homolog enriched in brain SCG2: Secretogranin II SEMA7A: Semaphorin 7A (John Milton Hagen blood group) SEMAG4G: Semaphorin-4G SERT: Serotonin transporter SERTAD1: SERTA domain containing 1 SGK1: Serum/glucocorticoid regulated kinase 1 SH3KBP1: SH3 domain containing kinase binding protein 1 SIK1: Salt inducible kinase
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  • Visualizing Locus-Speciic Sister Chromatid Exchange Reveals Differential Patterns of Replication Stress-Induced Fragile Site Breakage

    Visualizing Locus-Speciic Sister Chromatid Exchange Reveals Differential Patterns of Replication Stress-Induced Fragile Site Breakage

    Oncogene (2020) 39:1260–1272 https://doi.org/10.1038/s41388-019-1054-5 ARTICLE Visualizing locus-specific sister chromatid exchange reveals differential patterns of replication stress-induced fragile site breakage 1 1 1 1 1,2 Irina Waisertreiger ● Katherine Popovich ● Maya Block ● Krista R. Anderson ● Jacqueline H. Barlow Received: 16 November 2018 / Revised: 26 September 2019 / Accepted: 2 October 2019 / Published online: 21 October 2019 © The Author(s) 2019. This article is published with open access Abstract Chromosomal fragile sites are genomic loci sensitive to replication stress which accumulate high levels of DNA damage, and are frequently mutated in cancers. Fragile site damage is thought to arise from the aberrant repair of spontaneous replication stress, however successful fragile site repair cannot be calculated using existing techniques. Here, we report a new assay measuring recombination-mediated repair at endogenous genomic loci by combining a sister chromatid exchange (SCE) assay with fluorescent in situ hybridization (SCE-FISH). Using SCE-FISH, we find that endogenous and exogenous replication stress generated unrepaired breaks and SCEs at fragile sites. We also find that distinct sources of replication stress 1234567890();,: 1234567890();,: induce distinct patterns of breakage: ATR inhibition induces more breaks at early replicating fragile sites (ERFS), while ERFS and late-replicating common fragile sites (CFS) are equally fragile in response to aphidicolin. Furthermore, SCEs were suppressed at fragile sites near centromeres in response to replication stress, suggesting that genomic location influences DNA repair pathway choice. SCE-FISH also measured successful recombination in human primary lymphocytes, and identificed the proto-oncogene BCL2 as a replication stress-induced fragile site.
  • Platform Abstracts

    Platform Abstracts

    American Society of Human Genetics 65th Annual Meeting October 6–10, 2015 Baltimore, MD PLATFORM ABSTRACTS Wednesday, October 7, 9:50-10:30am Abstract #’s Friday, October 9, 2:15-4:15 pm: Concurrent Platform Session D: 4. Featured Plenary Abstract Session I Hall F #1-#2 46. Hen’s Teeth? Rare Variants and Common Disease Ballroom I #195-#202 Wednesday, October 7, 2:30-4:30pm Concurrent Platform Session A: 47. The Zen of Gene and Variant 15. Update on Breast and Prostate Assessment Ballroom III #203-#210 Cancer Genetics Ballroom I #3-#10 48. New Genes and Mechanisms in 16. Switching on to Regulatory Variation Ballroom III #11-#18 Developmental Disorders and 17. Shedding Light into the Dark: From Intellectual Disabilities Room 307 #211-#218 Lung Disease to Autoimmune Disease Room 307 #19-#26 49. Statistical Genetics: Networks, 18. Addressing the Difficult Regions of Pathways, and Expression Room 309 #219-#226 the Genome Room 309 #27-#34 50. Going Platinum: Building a Better 19. Statistical Genetics: Complex Genome Room 316 #227-#234 Phenotypes, Complex Solutions Room 316 #35-#42 51. Cancer Genetic Mechanisms Room 318/321 #235-#242 20. Think Globally, Act Locally: Copy 52. Target Practice: Therapy for Genetic Hilton Hotel Number Variation Room 318/321 #43-#50 Diseases Ballroom 1 #243-#250 21. Recent Advances in the Genetic Basis 53. The Real World: Translating Hilton Hotel of Neuromuscular and Other Hilton Hotel Sequencing into the Clinic Ballroom 4 #251-#258 Neurodegenerative Phenotypes Ballroom 1 #51-#58 22. Neuropsychiatric Diseases of Hilton Hotel Friday, October 9, 4:30-6:30pm Concurrent Platform Session E: Childhood Ballroom 4 #59-#66 54.