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The Role of Rfx Transcription Factors in Neurons and in the Human Brain

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The Role of Rfx Transcription Factors in Neurons and in the Human Brain From the DEPARTMENT OF BIOSCIENCES AND NUTRITION Karolinska Institutet, Stockholm, Sweden THE ROLE OF RFX TRANSCRIPTION FACTORS IN NEURONS AND IN THE HUMAN BRAIN Debora Sugiaman-Trapman Stockholm 2018 All previously published papers, figures and tables were reproduced with permission. Cover illustration by the author, titled “How I Imagine”. Some cartoon figures were taken from the internet (Accessed 7 May 2018), namely the human brain (Shutterstock 69563776), the Hedgehog signaling (Richard Wheeler, Calculated Images), and the Monas Tower of Jakarta (Freepik, Flaticon). Published by Karolinska Institutet Printed by E-Print AB 2018 © Debora Sugiaman-Trapman, 2018 ISBN 978-91-7831-043-2 The role of RFX transcription factors in neurons and in the human brain THESIS FOR DOCTORAL DEGREE (Ph.D.) By Debora Sugiaman-Trapman Friday the 28th of September, 2018 at 09:30 Lecture Hall 9Q Månen, Alfred Nobels allé 8, Huddinge Campus Flemingsberg Principal Supervisor: Opponent: Prof. Juha Kere Prof. Andrew Jarman Karolinska Institutet University of Edinburgh Department of Biosciences and Nutrition Centre for Discovery Brain Sciences Co-supervisor: Examination Board: Dr. Peter Swoboda Prof. Mattias Mannervik Karolinska Institutet Stockholm University Department of Biosciences and Nutrition Department of Molecular Biosciences The Wenner-Gren Institute Prof. Maria Eriksson Karolinska Institutet Department of Biosciences and Nutrition Assoc. Prof. Helena Karlström, Docent Karolinska Institutet Department of Neurobiology, Care Sciences and Society To my father, Djonady Sugiaman ABSTRACT RFX transcription factors (TFs) are conserved in animals, fungi and some amoebae, but not in algae, plants and protozoan species. The conservation is based on the protein sequence of the DNA binding domain (DBD). The RFX DBD recognizes and binds to a DNA sequence motif called the X-box. In addition to the DBD, most RFX TFs have a Dimerization domain (DIM). The DIM enables RFX TFs to form homo- or heterodimers in detecting the X-box motif, rendering the X-box often described as an imperfect palindromic sequence of two 6-bp half-sites with variable spacers. So far, RFX TFs are known to regulate gene transcription in cell cycle, DNA repair, immune response, collagen transcription, insulin production, spermatogenesis and hearing. In animals, the most common feature of RFX TFs is their regulation of ciliogenesis and the maintenance of specialized functions of ciliated cells. Cilia are hair-like cell protrusions. They are present in all animals but absent in many species of fungi, amoebae and flowering plants. Based on the inner structure, cilia can be divided into two types, the primary cilia (one cilium per cell) and the motile cilia (either as mono-cilia or multiple-cilia per cell). The primary cilia are less understood despite being present on nearly every cell in the human body. Humans have eight RFX genes (RFX1-8) which are expressed in diverse tissues and cell types. This thesis serves to expand knowledge of the RFX TF family in humans and their role in primary cilia and neurons, with interest in human brain development and function. We used databases (Paper I), human cell lines (Papers I and II) and the worm C. elegans (Paper III) as our materials for experimentation. In Paper I, we performed an extensive survey of RFX1-8 expression by transcription start site (TSS) counts from the FANTOM5 database. RFX1-4 and RFX7 are prominently expressed in different brain tissues and spinal cord, making them the reference RFX TFs for neurons and the human brain. Furthermore, we predicted the regulation preference of RFX TFs based on co-clustering expression analysis with known RFX target genes. We also analyzed the positioning of the X-box motifs in the human genome and uncovered potential upstream regulators of RFX genes. In Paper II, we explored the role of RFX TFs in the context of developmental dyslexia, a developmental disorder of the human brain. The dyslexia candidate genes DYX1C1, DCDC2 and KIAA0319 have functional X-box motifs in their promoter regions, as shown by luciferase reporter assay of wild-type versus mutated X-boxes. By siRNA knockdowns of RFX1-3, we showed a complex regulatory mechanism among RFX1-3 in regulating DYX1C1 and DCDC2. Additionally, both DYX1C1 and DCDC2 localize to the primary cilia. In Paper III, we performed microarray analysis of target genes of DAF-19, the sole RFX TF of C. elegans, at three developmental stages (3-fold embryo, L1-larvae and adult). At all stages, DAF-19-regulated target genes were significantly enriched in neurons. Using transcriptional GFP reporter constructs, we observed that DAF-19-dependent target genes (both activated and repressed) affected only neurons, both ciliated and non-ciliated. Altogether, we provided insight into the role of RFX TFs for primary cilia and neurons. We speculate that RFX TFs and primary cilia continue to play a defined role for mature neuron function in the human brain. LIST OF ORIGINAL PUBLICATIONS The thesis is based on the following articles or papers, which are referred in the text as Paper I, Paper II and Paper III, respectively. I. Sugiaman-Trapman D, Vitezic M, Jouhilahti EM, Mathelier A, Lauter G, Misra S, Daub CO, Kere J, Swoboda P. Characterization of the human RFX transcription factor family by regulatory and target gene analysis. BMC Genomics. 2018 Mar 6;19(1):181. II. Tammimies K*, Bieder A*, Lauter G*, Sugiaman-Trapman D, Torchet R, Hokkanen ME, Burghoorn J, Castrén E, Kere J, Tapia-Páez I, Swoboda P. The ciliary dyslexia genes DYX1C1 and DCDC2 are regulated by RFX transcription factors through X-box promoter motifs. FASEB Journal. 2016 Oct;30(10):3578-3587. III. De Stasio EA, Mueller KP, Bauer RJ, Hurlburt AJ, Bice SA, Scholtz SL, Prasad Phirke, Sugiaman-Trapman D, Stinson LA, Olson HB, Vogel SL, Ek- Vazquez Z, Esemen Y, Korzynski J, Wolfe K, Arbuckle BN, Zhang H, Lombard-Knapp G, Piasecki BP, Swoboda P. An expanded role for the RFX transcription factor DAF-19, with dual functions in ciliated and non-ciliated neurons. Genetics. 2018 Mar;208(3):1083-1097. *Authors contributed equally CONTENTS 1 Introduction ..................................................................................................................... 5 1.1 RFX transcription factors ...................................................................................... 5 1.1.1 RFX TFs are evolutionarily conserved ..................................................... 6 1.1.2 RFX TFs recognize and bind X-box motifs ............................................. 6 1.1.3 RFX target gene modules.......................................................................... 7 1.1.4 Regulators of RFX genes .......................................................................... 9 1.2 Cilia and Ciliopathies ............................................................................................ 9 1.2.1 Cilia architecture and intraflagellar transport (IFT) ............................... 10 1.2.2 Primary cilia, centrioles and cell cycle progression ............................... 11 1.2.3 Cilia in vertebrates .................................................................................. 12 1.2.4 Ciliopathies in the nervous system and the brain ................................... 13 1.3 RFX TFs and the vertebrate nervous system ...................................................... 14 1.3.1 Expression of Rfx in the mouse, frog and fish nervous systems ............ 15 1.3.2 Phenotypes of Rfx deficient mice ........................................................... 16 1.4 DAF-19, the sole RFX TF in C. elegans ............................................................ 17 1.4.1 Cilia in the invertebrate C. elegans ......................................................... 19 1.4.2 DAF-19 in C. elegans neurons ............................................................... 20 1.4.3 Phenotypes of daf-19 mutants................................................................. 21 2 Aims ............................................................................................................................... 23 3 Results ............................................................................................................................ 25 3.1 Paper I .................................................................................................................. 25 3.2 Paper II ................................................................................................................. 26 3.3 Paper III ............................................................................................................... 28 4 Discussion ...................................................................................................................... 31 5 Methodological Considerations .................................................................................... 33 5.1 Databases of Transcriptome and TF-binding Profiles ........................................ 33 5.1.1 FANTOM5 database (Paper I) ................................................................ 33 5.1.2 JASPAR database (Paper I) .................................................................... 33 5.2 Cell Lines and Animal Model ............................................................................. 33 5.2.1 Human cell lines (Papers I and II) .......................................................... 33 5.2.2 C. elegans animal model (Paper III) ....................................................... 34 6 Concluding Remarks
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