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Trappc9 Gene INVESTIGATIONS INTO THE FUNCTIONS AND REGULATION OF THE MICROCEPHALY-ASSOCIATED TRAPPC9 GENE. Thesis written in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy By Michela Pulix April 2017 2 DECLARATION I hereby declare that except where specific reference is made to the work of others, the contents of this thesis are original and have not been submitted in whole or in part for consideration for any other degree or qualification in this or any other university. This dissertation is my own work and contains nothing which is the outcome of work done in collaboration with others except as specified in the text. This dissertation contains fewer than 65,000 words including bibliography, footnotes, tables and equations and has fewer than 70 figures. Michela Pulix April 2017 3 4 Abstract Trafficking Protein Particle Complex 9 (Trappc9) belongs to the TRAPPII multiprotein complex involved in vesicular trafficking and tethering. Loss-of-function mutations in the sequence of TRAPPC9 have been shown to cause autosomal recessive non-syndromic intellectual disability. Characteristic symptoms among the affected individuals are dysmorphic facial features, speech delay and inability to feed themselves. Postnatal microcephaly is accompanied by agenesis of the corpus callosum, white matter abnormalities and reduced cerebellar volume. It has been shown that Trappc9 promotes the activation of the NF-κB pathway and the NGF-induced neurite outgrowth in PC12 cells. Furthermore, it has been shown to interact with p150glued (subunit of dynactin) and its depletion causes the accumulation of aberrantly large lipid droplets. Furthermore, this gene is located in the imprinted Peg13/Kcnk9 gene cluster. Genomic imprinting regulates gene expression in a parent-of-origin specific manner through epigenetic mechanisms, thus resulting in preferential transcription from either the maternal or paternal allele. Conflicting reports have been published on the imprinting status of Trappc9. This thesis investigates a number of aspects on the genetic regulation and cellular functions of Trappc9. It also provides a first characterisation of a novel knockout (KO) mouse model for Trappc9. Chapter 3 describes the genetic structure and regulation of murine Trappc9. I demonstrated that only one transcript variant, with an alternatively spliced exon, is 5 produced from this gene in contrast to the information available on genomic databases. I also confirmed the imprinted expression of Trappc9 in the mouse brain, where it shows a 70% preferential expression from the maternal allele, while a biallelic expression was found in peripheral tissues. Using a range of techniques, I also demonstrated a gradient of methylation within a CpG island located in the promoter region of murine Trappc9, which appears to be unrelated to the regulation of imprinting. Chapter 4 is focussed on the molecular and cellular functions of Trappc9. As this protein has previously been linked with the NF-κB pathway and NGF-induced neurite outgrowth in PC12 cells, I tried to replicate some of the results found in the literature. Using siRNA gene silencing I created a transient knockdown for Trappc9 in PC12 cells. Unfortunately, as the differentiation of these cells reaches optimal results in 9 days, the design of the assay was not optimal to study the effect of neurite outgrowth in this cell line. As an alternative to studying the role of Trappc9 in neurite elongation, I created a stable N2A knockdown cell line via shRNA lentivirus transduction, with 50-60% reduction of Trappc9 expression. N2A cells do not respond to NGF but differentiate in the presence of retinoic acid. Under such conditions I found that Trappc9-depleted cells tend to differentiate into cells with a reduced number of neurites, suggesting defects in neuronal differentiation might be the basis of TRAPPC9-induced microcephaly. Chapter 5 describes the analysis of a novel Trappc9 KO mouse model. These mice carry a knock-in gene trap, containing a LacZ reporter gene, within an intron of Trappc9 that causes a frameshift and premature interruption of transcription. Although the LacZ is not translated into a functional β-Galactosidase due to unexpected splicing events, I have confirmed that these mice have lost Trappc9 protein expression and found that they develop a mild microcephaly phenotype at 12 weeks of age. I also found an increase in body weight in female mice, similarly to what has been found in two human patients with 6 mutations in TRAPPC9. Immunohistochemical analysis of brain sections revealed KO mice possess a reduced number of cells positive for the progenitor cell marker Sox-2 in the dentate gyrus of the hippocampus. Preliminary results also highlighted a reduction in cells positive for the astrocyte marker GFAP in the corpus callosum and hypothalamus. Finally, chapter 6 focuses on human TRAPPC9. I identified Variable Number Tandem Repeat (VNTR) polymorphisms within the promoter region of TRAPPC9, which appears to be an important regulatory region as it is a predicted G-quadruplex and is rich in CTCF binding sites. The three observed variants possess the ability to induce gene expression in a luciferase reporter gene assay in SH-SY5Y neuroblastoma cells but not in kidney-derived HEK293 cells, suggesting a cell specific function of these VNTRs. In conclusion, Trappc9 is required for normal brain function in mice and the KO mouse model can be used to investigate the underlying molecular and cellular mechanisms relevant for the associated human neurodevelopmental disorder. Further investigations of this gene and its role in development will be beneficial in order to understand the mechanisms of microcephaly and intellectual disability. 7 Table of Contents Abstract ............................................................................................................................................................................................ 5 List of Figures ............................................................................................................................................................................. 12 List of Tables ............................................................................................................................................................................... 13 List of Abbreviations ............................................................................................................................................................... 14 CHAPTER 1 ...................................................................................................................................................................................... 17 Introduction ................................................................................................................................................................................ 17 1.1 Epigenetics ...................................................................................................................................................................... 17 1.1.1 Definition and mechanisms ............................................................................................................................. 17 1.1.2 Chromatin structure and epigenetic indicators of chromatin state .............................................. 18 1.1.3 Variable Tandem Number Repeats (VNTRs) and associated disorders...................................... 20 1.1.4 DNA secondary structures ............................................................................................................................... 23 1.2 Genomic imprinting .................................................................................................................................................... 27 1.2.1 History and definition ........................................................................................................................................ 27 1.2.2 Establishment and regulation of imprinting ........................................................................................... 30 1.2.3 Imprinted genes and human disorders...................................................................................................... 34 1.2.4 Peg13/KCNK9 gene cluster ............................................................................................................................. 36 1.3 Microcephaly and TRAPPC9-related disorder ................................................................................................ 38 1.3.1 Definition and causes of microcephaly ...................................................................................................... 38 1.3.2 Postnatal microcephaly-associated disorders ........................................................................................ 41 1.3.3 TRAPPC9 mutations in humans .................................................................................................................... 42 1.4 Trappc9-associated pathways and systems in the cell ................................................................................ 44 1.4.1 TRAPP complexes and vesicle tethering ................................................................................................... 44 1.4.2 NF-κB pathway ..................................................................................................................................................... 47 1.4.3 Cellular functions of Trappc9 ........................................................................................................................
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