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The Mediator Complex, Which Is Thought to Function As an Accessory Repressor Or Activator of Mediator

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The Mediator Complex, Which Is Thought to Function As an Accessory Repressor Or Activator of Mediator REGULATION OF STRIATED MUSCLE METABOLISM AND FUNCTION BY MEDIATOR COMPLEX APPROVED BY SUPERVISORY COMMITTEE Eric N. Olson, Ph.D. Steven A. Kliewer, Ph.D. James T. Stull, Ph.D. Ondine Cleaver, Ph.D. Dedicated to my parents REGULATION OF STRIATED MUSCLE METABOLSIM AND FUNCTION BY MEDIATOR COMPLEX by SUSAN M. DELEON DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center at Dallas Dallas, Texas August, 2015 Copyright 2015 By Susan M. DeLeon, 2015 All Rights Reserved REGULATION OF STRIATED MUSCLE METABOLSIM AND FUNCTION BY MEDIATOR COMPLEX SUSAN M. DELEON, Ph.D. The University of Texas Southwestern Medical Center at Dallas, 2015 Supervising Professor: Eric N. Olson, Ph.D. Mediator is a multi-protein complex that links signal-dependent transcription factors and upstream regulators with polymerase II (Pol II) to form a stable and efficient pre-initiation complex (PIC). Recent studies have suggested that different compositions of subunits in Mediator in a cell-specific and signal-dependant manner, which permits customizable regulation of different subsets of genes, and variable responses to signals from transcription factors. In this way, Mediator allows for response to the continuous changes of the cellular environment. Our studies have implicated the mediator subunit v MED13 in the control of cardiac and skeletal muscle metabolism. MED13, along with MED12, cyclin C and cdc8, form the kinase module of the Mediator complex, which is thought to function as an accessory repressor or activator of Mediator. To investigate the potential role of MED12 in striated muscle functions, we generated mice with conditional deletion of MED12 in the heart and skeletal muscle. Mice with cardiac deletion of MED12 display postnatal cardiomyopathy with dysregulation of genes involved in calcium homeostasis and contractility. Mice with skeletal muscle deletion of MED12 show severe muscle defects and a failure to thrive, which likely reflects a role of this Mediator subunit in the control of muscle growth. Collectively, these highlight distinct roles of the kinase module of the Mediator complex in cardiac and skeletal muscle development and function. vi TABLE OF CONTENTS TITLE ..................................................................................................................................... i DEDICATION ....................................................................................................................... ii ABSTRACT ........................................................................................................................... v TABLE OF CONTENTS ...................................................................................................... vii LIST OF PUBLICATIONS ................................................................................................... x LIST OF FIGURES .............................................................................................................. xi LIST OF TABLES .............................................................................................................. xiii LIST OF ABBREVIATIONS .............................................................................................. xv CHAPTER I ...................................................................................................................... 1 Striated Muscle Development and Function ..................................................................... 1 Introduction ...................................................................................................................... 1 The sarcomere and striated muscle contractility ...................................................... 1 Heart disease, muscle function, and metabolism ...................................................... 5 Concluding Remarks ...................................................................................................... 13 CHAPTER II .................................................................................................................. 14 The Mediator Complex: A Master Transcriptional Coordinator .................................. 14 Introduction .................................................................................................................... 14 Mediator overview ................................................................................................. 15 Mediator in striated muscle .................................................................................... 17 Concluding Remarks ...................................................................................................... 21 CHAPTER III ................................................................................................................ 22 Cardiac Mediator Subunit MED13 Signaling Governs Systemic Metabolism ............. 22 Abstract .......................................................................................................................... 22 Introduction .................................................................................................................... 23 vii Results ............................................................................................................................ 24 Cardiac-specific overexpression of Med13 prevents obesity and improves glucose tolerance .................................................................................................... 24 Cardiac deletion of Med13 enhances susceptibility to obesity .............................. 26 MED13 modulates systemic energy consumption .................................................. 31 Down-regulation of Nuclear Hormone Receptor target genes by Med13 ............... 31 Discussion ...................................................................................................................... 35 Methods .......................................................................................................................... 39 CHAPTER IV ................................................................................................................ 42 MED12 Regulates Expression of Genes Involved in Contractility in Cardiac Tissue .. 42 Introduction .................................................................................................................... 42 Results ............................................................................................................................ 44 Cardiac-specific deletion of MED12 leads to dilated cardiomyopathy and impaired cardiac function ....................................................................................... 45 Changes in contractile gene expression associated with cardiac depletion of MED12 ................................................................................................................... 46 Cardiomyocytes lacking Med12 have enhanced calcium handling ........................ 48 Discussion ...................................................................................................................... 51 Methods .......................................................................................................................... 53 CHAPTER V .................................................................................................................. 58 Regulation of Skeletal Muscle Gene Expression and Performance by MED12 ............ 58 Introduction .................................................................................................................... 58 Results ............................................................................................................................ 58 Skeletal muscle-specific deletion of MED12 causes postnatal lethality and failure to thrive ................................................................................................................... 60 Med12-deficient skeletal muscle has abnormal structure and function ................. 61 viii Loss of MED12 in skeletal muscle leads to dysregulation of several transcription factor pathways ........................................................................................................ 62 MED12-deficient skeletal muscle exhibits failure to hypertrophy ......................... 67 Metabolic defects in MED12-deficient skeletal muscle .......................................... 68 Discussion ...................................................................................................................... 70 Methods .......................................................................................................................... 72 CHAPTER VI ................................................................................................................ 79 Conclusions and Further Remarks ................................................................................... 79 APPENDIX ........................................................................................................................... 84 REFERENCES .................................................................................................................... 85 ix PRIOR PUBLICATIONS Caldwell, K.A., Tucci, M.L., Armagost, J., Hodges, T.W., Chen, J., Memon, S.B., Blalock, J.E., DeLeon, S.M., Findlay, R.H., Ruan, Q., Webber, P.J., Standaert,
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