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Grimme, Acadia.Pdf MECHANISM OF ACTION OF HISTONE DEACETYLASE INHIBITORS ON SURVIVAL MOTOR NEURON 2 PROMOTER by Acadia L. Grimme A thesis submitted to the Faculty of the University of Delaware in partial fulfillment of the requirements for the degree of Bachelors of Science in Biological Sciences with Distinction Spring 2018 © 2018 Acadia Grimme All Rights Reserved MECHANISM OF ACTION OF HISTONE DEACETYLASE INHIBITORS ON SURVIVAL MOTOR NEURON 2 PROMOTER by Acadia L. Grimme Approved: __________________________________________________________ Matthew E. R. Butchbach, Ph.D. Professor in charge of thesis on behalf of the Advisory Committee Approved: __________________________________________________________ Deni S. Galileo, Ph.D. Professor in charge of thesis on behalf of the Advisory Committee Approved: __________________________________________________________ Carlton R. Cooper, Ph.D. Committee member from the Department of Biological Sciences Approved: __________________________________________________________ Gary H. Laverty, Ph.D. Committee member from the Board of Senior Thesis Readers Approved: __________________________________________________________ Michael Chajes, Ph.D. Chair of the University Committee on Student and Faculty Honors ACKNOWLEDGMENTS I would like to acknowledge my thesis director Dr. Butchbach for his wonderful guidance and patience as I worked through my project. He has been an excellent research mentor over the last two years and I am forever thankful that he welcomed me into his lab. His dedication to his work inspires me as an aspiring research scientist. His lessons will carry on with me as I pursue future research in graduate school and beyond. I would like to thank both current and former members of the Motor Neuron Disease Laboratory: Sambee Kanda, Kyle Hinkle, and Andrew Connell. Sambee and Andrew patiently taught me many of the techniques I utilized in my project, and without them it would not be what it is today. All members of the lab offered me support and encouragement throughout my work on my thesis, and I am grateful that I got to work alongside them. I would like to thank the other members of my thesis committee, Dr. Galileo, Dr. Laverty, and Dr. Cooper for their time and dedication to supporting me and other undergraduate researchers. The three classes I had with Dr. Galileo played a major role in shaping my future research pursuits, and I am delighted to have had him as a professor as well as committee member. Finally, I would like to thank my family and friends. Most of them are not biology-oriented individuals, but they listened to and supported me throughout my work on my thesis. Their love helps to keep me going. iii TABLE OF CONTENTS LIST OF TABLES ........................................................................................................ vi LIST OF FIGURES ...................................................................................................... vii ABSTRACT ................................................................................................................ viii Chapter 1 INTRODUCTION .............................................................................................. 1 1.1 Spinal Muscular Atrophy and SMN ........................................................... 1 1.2 The Histone Code ...................................................................................... 4 1.3 Histone Deacetylase Inhibitors .................................................................. 6 1.4 Project Aims and Hypothesis .................................................................... 8 2 METHODS ....................................................................................................... 10 2.1 Drug Compounds .................................................................................... 10 2.2 Cell Culture ............................................................................................. 10 2.3 β-Lactamase Reporter Assay ................................................................... 10 2.4 Drug Treatment ....................................................................................... 11 2.5 Quantitative Reverse Transcriptase PCR ................................................ 11 2.6 Transient Transfection of NSC-34 .......................................................... 12 2.7 Chroma Glo Luciferase Reporter Assay ................................................. 12 2.8 Promoter Analysis ................................................................................... 14 2.9 Statistics ................................................................................................... 14 3 RESULTS ......................................................................................................... 15 3.1 Effects of HDAC inhibitors on Smn mRNA transcript levels ................. 15 3.2 Assessment of SMN2 Promoter Luciferase Constructs ........................... 16 3.3 Effect of HDAC inhibitor treatment on SMN2 Dual Luciferase Assay .. 19 3.4 Promoter Analysis of SMN2 constructs ................................................... 21 3.5 Effect of HDAC inhibitor treatment on SMN2 β-Lactamase Promoter Assay ....................................................................................................... 24 4 DISCUSSION ................................................................................................... 26 5 CONCLUSION AND FUTURE DIRECTION ................................................ 30 iv REFERENCES ............................................................................................................. 32 v LIST OF TABLES Table 1.1: HDAC inhibitors previously tested for SMA applications. ...................... 7 Table 3.1. List of Putative Transcription Factors in SMN2 Promoter Constructs. ... 22 vi LIST OF FIGURES Figure 1.1 Exon 7 inclusion is required for functional SMN protein levels. .............. 2 Figure 1.2 Representation of the dynamic modifications of histone tails. ................. 5 Figure 3.1 Effect of HDAC inhibitors on fold change of Smn mRNA levels.. ........ 16 Figure 3.2 Verifying CBR and CBG68 Signaling in NSC-34 cells. ......................... 17 Figure 3.3 Basal activity of SMN2 Luciferase Constructs in NSC-34s. ................... 18 Figure 3.4 Effects of HDAC inhibitor treatment on SMN2 dual luciferase assay. ... 20 Figure 3.5 Effect of TSA treatment on alternative CBG68 vectors. ......................... 21 Figure 3.6 SMN2 promoter activity under HDAC inhibitor treatment.. ................... 25 vii ABSTRACT Spinal muscular atrophy (SMA) is an early-onset recessive neurodegenerative disease that primarily affects the α-motor neurons in the anterior horn of the spinal cord. The degeneration of these motor neurons leads to gradual muscular atrophy, eventual respiratory complications, and early death in severe types of SMA. Due to deletion or mutation events, patients with SMA lack a functional copy of the Survival Motor Neuron 1 (SMN1) gene. Humans however have a nearly identical copy of SMN1 known as Survival Motor Neuron 2 (SMN2), which is retained in SMA patients. The major difference between SMN1 and SMN2 is that SMN2 contains a nucleotide substitution in exon 7 that results in the exclusion of this exon in the majority of mRNA transcripts produced from SMN2. This exclusion of exon 7 results in low levels of functional SMN protein. In animal models and within patient populations, it has been shown that increasing SMN2 copy number results in a less severe SMA phenotype, making SMN2 an ideal target for SMA therapeutics. Histone deacetylase (HDAC) inhibitors have been extensively studied for treatment of SMA through increasing transcription of the SMN2 gene; however, several of these HDAC inhibitors demonstrated a highly variable patient response and possible toxicity. In this project, I examine the HDAC inhibitors RGFP106, RGFP109, CAY10433, and HDACi-IV to determine their potential for increasing SMN2 transcription and develop a SMN2 promoter dual luciferase assay for studying the potential mechanism of action of these drug compounds. These compounds were selected to study as they have shown positive effects on SMN2 expression in human SMA fibroblast cell lines. RGFP106 viii and RGFP109 increased transcription of Smn in NSC-34 motor neuron-like cells. The preliminary test of the SMN2 dual luciferase assay showed that all test compounds activated the SMN2 promoter, but this data was possibly skewed due to concurrent up- regulation of the TK promoter control. My drug compounds of interest failed to significantly increase promoter activation in a SMN2 β-lactamase promoter assay. My findings indicate that these HDAC inhibitors may not act on the SMN2 promoter through direct transcription factor based activity, thus an alternative mechanism must be explored. ix Chapter 1 INTRODUCTION 1.1 Spinal Muscular Atrophy and SMN Spinal muscular atrophy (SMA) is an early-onset recessive neurodegenerative disease in which the α-motor neurons of the anterior horn of the spinal cord and lower brainstem are lost (Crawford and Pardo, 1996). This loss results in the atrophy of the limb and trunk muscles, leading to eventual respiratory complications and a shortened lifespan. SMA has a high incidence rate of approximately 1 in 10,000 live births (Cuscó et al., 2002) and, as a result, is one of the leading genetics causes of infant death. There are five clinical grades of SMA, ranging from the most severe Type 0 to the mildest Type IV, which are assigned on the basis of disease
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