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Molecular Analysis of the Mechanisms Involved in THBS4 Differential Gene- Expression in the Human Brain

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Molecular Analysis of the Mechanisms Involved in THBS4 Differential Gene- Expression in the Human Brain Molecular analysis of the mechanisms involved in THBS4 differential gene- expression in the human brain. Análisis molecular de los mecanismos implicados en las diferencias de expresión del gen THBS4 en el cerebro humano. DOCTORAL THESIS Raquel Rubio Acero Universitat Autònoma de Barcelona Facultat de Biociències Departament de Genètica i de Microbiologia Bellaterra, 2013 Memoria presentada por la Licenciada en Biología Raquel Rubio Acero para optar al grado de Doctora en Biología. Raquel Rubio Acero Bellaterra, 16 de octubre de 2013 El Doctor Mario Cáceres Aguilar, Profesor de Investigación ICREA del Institut de Biotecnologia i de Biomedicina de la Universitat Autònoma de Barcelona, CERTIFICA que Raquel Rubio Acero ha llevado a cabo bajo su dirección el trabajo de investigación realizado en el Departamento de Genética y de Microbiología de la Facultad de Biociencias de la Universitat Autònoma de Barcelona y que ha dado lugar a la elaboración de esta Tesis Doctoral titulada “Molecular analysis of the mechanisms involved in THBS4 differential gene-expression in the human brain”. Y para que conste a los efectos oportunos, firma el presente comunicado en Bellaterra, a 16 de octubre de 2013. Dr. Mario Cáceres Aguilar TABLE OF CONTENTS ABSTRACT | RESUMEN....................................................................................... 13 1. INTRODUCTION............................................................................................. 17 1.1. What makes us humans?........................................................................ 19 1.1.1. The human brain and its evolution. 21 1.1.2. Anatomical modifications and diseases. 24 1.1.3. Spot the difference: from phenotype to genes. 25 1.1.3.1. Large-scalecytogenetic changes. 26 1.1.3.2. Structural changes. 27 1.1.3.3. Small genetic changes. 29 1.1.3.4. Changes in gene expression. 30 1.2. Regulatory evolution of the gene expression........................................... 34 1.2.1. The role of regulatory mutations in the evolution. 34 1.2.2. Possible mechanishms of gene regulation. 37 1.2.1.1. Genomic structural variations. 37 1.2.1.2. Regulatory changes in cis. 38 1.2.1.3. Regulatory changes in trans. 40 1.2.1.4. Epigenetic chromatin modifications. 41 1.2.1.5. Modifications of the mRNA. 42 1.3. Methods for characterization of regulatory regions................................. 43 1.3.1. What is a promoter? 44 1.3.2. Other types of regulatory elements. 47 1.3.2.1. Enhancers and silencers. 47 1.3.2.2. Insulators. 48 1.3.2.3. microRNA binding sites. 48 1.3.3. Computational characterization of promoter regions and other regulatory elements. 49 1.3.4. Experimental characterization of regulatory elements. 51 1.4. The thrombospondin family.................................................................. 54 1.4.1. Functions of thrombospondins and their implication in the central nervous system. 55 1.4.2. The thrombospondin-4 gene. 58 1.4.2.1. Gene expression analysis in THBS4. 58 1.4.2.2. Cellular localization of THBS4. 60 1.4.2.3. Known effects of THBS4 SNPs. 60 1.5. Objectives 62 2. MATERIALS AND METHODS........................................................................... 65 2.1. Samples................................................................................................. 67 2.1.1. Commercial RNAs. 67 2.1.2. Cell lines. 69 2.1.3. Tissues. 70 2.1.3.1. Tissues collection. 73 2.2. Nucleic acid isolation............................................................................. 75 2.3. Cell-line culture and media.................................................................... 76 2.4. RT-PCR and PCR................................................................................. 77 2.5. Cloning and transformation................................................................... 79 2.5.1. Cloning into pGL3 Vectors. 79 2.5.2. Cloning into pGEM-T Vectors. 83 2.6. Sanger sequencing.................................................................................. 84 2.7. Real-Time RT-PCR................................................................................ 85 2.8. Luciferase assay...................................................................................... 86 2.9. DNA methylation analysis..................................................................... 88 2.10. ChIP-Seq............................................................................................. 91 2.11. Bioinformatic prediction of enhancers................................................. 93 2.12. Allele-specific expression quantification................................................ 95 2.12.1. AS-PCR. 95 2.12.2. Pyrosequencing. 96 2.13. Common bioinformatic analysis........................................................... 97 3. RESULTS......................................................................................................... 99 3.1. Computational characterization of THBS4 regulatory changes.............. 101 3.1.1. The THBS4 genomic context. 102 3.1.2. Identification of the THBS4 promoter. 104 3.1.3. Other THBS4 transcripts. 107 3.2. Expression analysis of THBS4 promoters............................................. 110 3.2.1. THBS4 isoforms expression in human tissues. 110 3.2.2. Brain expression of THBS4 isoforms in primates. 112 3.3. Possible causes of THBS4 expression differences................................... 114 3.3.1. Interspecific differences in THBS4 promoters 114 3.3.2. Quantification of transcriptional activity of THBS4 promoters. 115 3.3.3. Searching for transcription factors binding sites near the THBS4 gene. 121 3.3.4. Analysis of promoter CpG methylation in primates. 124 3.4. Search and analysis of enhancers......................................................... 128 3.4.1. ChIP-Sequencing approach. 128 3.4.2. Computational prediction of enhancers. 132 3.4.3. Experimental validation of the predicted enhancers. 137 3.5. THBS4 expression variation in humans................................................. 140 3.6. Searching for insights about THBS4 promoters evolution..................... 144 4. DISCUSSION................................................................................................... 149 4.1. The study of human brain characteristics............................................... 151 4.2. The analysis of gene expression changes in the human brain ................. 157 4.3. The THBS4 gene.................................................................................. 162 4.3.1. Causes and consequences of THBS4 over-expression. 163 4.3.1.1. Possible effects acting in cis. 164 4.3.1.2. Potential epigenetic effects. 166 4.3.1.3. Potential effects acting in cis at longer distances 168 4.3.1.4. Limitations of the study. 171 4.3.2. The role of the alternative isoform. 174 4.3.3. The likely evolution of THBS4 promoters. 176 4.3.4. Balancing selection in humans: the two THBS4 haplotypes. 177 5. CONCLUSIONS............................................................................................... 181 APPENDIX I........................................................................................................ 187 Screenshots from the UCSC tracks and conservation between species of the different enhancer regions APPENDIX II....................................................................................................... 211 CAGLIANI, R., GUERINI, F.R., RUBIO-ACERO, R., BAGLIO, F., FORNI, D., AGLIARDI, C., GRIFFANTI, L., FUMAGALLI, M., POZZOLI, U., RIVA, S., CALABRESE, E., SIKORA, M., CASALS, F., COMI, G.P., BRESOLIN, N., CACERES, M., CLERICI, M. and SIRONI, M. (2013). "Long-Standing Balancing Selection in the THBS4 Gene: Influence on Sex-Specific Brain Expression and Gray Matter Volumes in Alzheimer Disease." Hum Mutat 34(5): 743-753. APPENDIX III..................................................................................................... 225 PRADO-MARTINEZ, J., HERNANDO-HERRAEZ, I., LORENTE-GALDOS, B., DABAD, M., RAMIREZ, O., BAEZA-DELGADO, C., MORCILLO-SUAREZ, C., ALKAN, C., HORMOZDIARI, F., RAINERI, E., ESTELLE, J., FERNANDEZ-CALLEJO, M., VALLES, M., RITSCHER, L., SCHONEBERG, T., DE LA CALLE- MUSTIENES, E., CASILLAS, S., RUBIO-ACERO, R., MELE, M., ENGELKEN, J., CACERES, M., GOMEZ- SKARMETA, J.L., GUT, M., BERTRANPETIT, J., GUT, I.G., ABELLO, T., EICHLER, E.E., MINGARRO, I., LALUEZA-FOX, C., NAVARRO, A. and MARQUES-BONET, T. (2013). "The genome sequencing of an albino Western lowland gorilla reveals inbreeding in the wild." BMC Genomics 14: 363. BIBLIOGRAPHY……………………………………………………………………………………… 235 ABBREVIATIONS……………………………………………………………………………………. 257 INDEX OF FIGURES…………………………………………………………………………………. 260 INDEX OF TABLES AND BOXES………………………………………………………………….. 262 AKNOWLEDGEMENTS | AGRADECIMIENTOS……………………………………………….. 264 A mi hermano, por considerarme tu mejor regalo. To my brother, for considering me your best gift. ABSTRACT The last decades have seen a growing interest in what makes us humans and how the human brain differs from that of our closest relatives at the molecular level. Hundreds of genes with expression differences between human and non-human primates have been identified. However, it is important to study these genes in more detail to see if they are really involved in human brain characteristics. Thrombospondins are multimeric extracellular glycoproteins that modulate cell-cell and extracellular matrix interactions and have been implicated in synaptogenesis. Within the thrombospondin family, thrombospondin-2 (THBS2) and thrombospondin-4 (THBS4) show, respectively, a ~2-fold and ~6-fold
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