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Crebh, a Novel Liver Clock Keeper for Energy Metabolism Ze Zheng Wayne State University Wayne State University Wayne State University Dissertations 1-1-2015 Crebh, A Novel Liver Clock Keeper For Energy Metabolism Ze Zheng Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Part of the Endocrinology Commons, Genetics Commons, and the Molecular Biology Commons Recommended Citation Zheng, Ze, "Crebh, A Novel Liver Clock Keeper For Energy Metabolism" (2015). Wayne State University Dissertations. Paper 1180. This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. CREBH, A NOVEL LIVER CLOCK KEEPER FOR ENERGY METABOLISM by ZE ZHENG DISSERTATION Submitted to the Graduate School of Wayne State University Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2015 MAJOR: MOLECULAR BIOLOGY AND GENETICS Approved By: Advisor Date © COPYRIGHT BY ZE ZHENG 2015 All Rights Reserved DEDICATION This work is dedicated to my parents and my husband Daochun Sun for their continuous support and understanding during the years of my education, and to my lovely little daughter Amber for her joyful and peaceful smiles to encourage me to complete this dissertation. I could not achieve my goal without them. ii ACKNOWLEDGMENTS I would like to express tremendous appreciation to my mentor, Dr. Kezhong Zhang. His encouragement and guidance throughout these years made this dissertation come true. I would also like to thank to my committee members, Dr. Gregory Kapatos for his sustained attention, inspiring discussions and generous supports from my course studies, lab rotation, to my thesis project, Dr. Todd Leff and Dr. Russel L. Finley for their informative class teaching, understanding and suggestions during these years. I gratefully acknowledge Dr. Maik Hüttemann and Dr. Li Li for their warm encouragements and supports during the toughest time of my oversea study, Dr. Guohui Wang and Dr. Chunbin Zhang for their patience and assistance with my experiments at the very beginning, Dr. Xuebao Zhang and Dr. Hyunbae Kim for teaching me the importance of precision in science. I sincerely recognize the wonderful inspiring discussions with visiting professor Dr. Kenji Fukudome, and the other two graduate students Mr. Roberto Mendez and Mr. Aditya Dandekar in lab. I also want to thank Mrs. Suzanne Shaw from CMMG administration, and Mrs. Becky Cai for their consideration and assistance throughout my study, and making my overseas education feel like home. iii TABLE OF CONTENTS DEDICATION ...................................................................................................................ii ACKNOWLEDGMENTS .................................................................................................. iii LIST OF TABLES ............................................................................................................vi LIST OF FIGURES ......................................................................................................... vii LIST OF ABBREVIATIONS .............................................................................................ix CHAPTER I: CREBH, a Liver Transcription Factor and More ......................................... 1 Introduction .................................................................................................................. 1 CREBH Gene Structure and Functions ........................................................................ 5 Transcriptional Regulation of CREBH ........................................................................ 10 CHAPTER II: Identification of CREBH as a Clock-regulated Diurnal Regulator in Liver 11 Summary.................................................................................................................... 11 Materials and Methods ............................................................................................... 13 Results ....................................................................................................................... 20 CHAPTER III: CREBH Functions under Circadian Rhythm ........................................... 28 Summary.................................................................................................................... 28 Materials and Methods ............................................................................................... 30 Results ....................................................................................................................... 33 iv CHAPTER IV: Crosstalk of CREBH and Other Circadian Regulators ........................... 52 Summary.................................................................................................................... 52 Materials and Methods ............................................................................................... 53 Results ....................................................................................................................... 55 REFERENCES .............................................................................................................. 72 ABSTRACT ................................................................................................................... 76 AUTOBIOGRAPHICAL STATEMENT ........................................................................... 78 v LIST OF TABLES Table 1. Primers for gene expression qPCR. ................................................................ 14 Table 2. Primers for ChIP-qPCR. .................................................................................. 18 Table 3. CRE binding motifs in the promoter regions of mouse genes.......................... 41 vi LIST OF FIGURES Figure 1. Major conclusions of this dissertation. .............................................................. 4 Figure 2. Domain scheme of human and mouse CREBH. .............................................. 5 Figure 3. CREBH-mediated signaling pathways. ............................................................ 9 Figure 4. CREBH is a clock-controlled gene (CCG) in mouse liver ............................... 22 Figure 5. Illustration of E-boxes in mouse CrebH gene promoter region. ...................... 23 Figure 6. CrebH is directly regulated by BMAL1 in mouse liver .................................... 25 Figure 7. CREBH is not a typical CCG. ......................................................................... 27 Figure 8. CREBH regulates rhythmic levels of circulating lipids in mice. ....................... 34 Figure 9. Levels of hepatic TG in CREBH-null and WT control mice livers. .................. 34 Figure 10. CREBH regulates rhythmic expression of the genes involved in lipolysis, FA oxidation, and lipogenesis in mice under the circadian clock. ....................................... 36 Figure 11. Rhythmic protein levels of the key metabolic enzymes or regulators in the livers of CREBH-null and WT control mice. ................................................................... 37 Figure 12. Slight alterations of metabolic gene rhythmic expressions in the livers of CREBH-null and WT control mice. ................................................................................ 38 Figure 13. CREBH regulates rhythmic levels of lipids and expression of the genes involved in lipolysis, FA oxidation, and lipogenesis in mice under the circadian clock. 40 Figure 14. CREBH regulates rhythmic levels of blood glucose and hepatic glycogen storage in mice under the circadian clock. .................................................................... 43 Figure 15. CREBH regulates rhythmic expression of the genes involved in gluconeogenesis and glycogenesis in mice under the circadian clock. ......................... 45 Figure 16. CREBH-null mice display hyper-locomotion and increased stereotypic activities during the night time. ...................................................................................... 48 Figure 17. CREBH deficiency leads to phase-shifted feeding behavior and increased metabolic rates. ............................................................................................................. 51 Figure 18. Rhythmic expression levels and amplitudes of core clock genes in the livers of CREBH-null and WT control mice. ............................................................................ 56 vii Figure 19. Rhythmic regulation of core clock proteins by CREBH in the liver. .............. 57 Figure 20. Rhythmic regulation of circadian transcriptional activators and repressor by CREBH in the liver. ....................................................................................................... 60 Figure 21. Rhythmic interactions between CREBH, the circadian transcriptional activators PPARα and C/EBPβ, and the repressor E4BP4 in the liver. ......................... 63 Figure 22. Potential CREBH-, PPARα-, C/EBPβ-, and E4BP4- binding sequences in the promoter region of mouse Pck1 gene. .......................................................................... 65 Figure 23. Rhythmic interactions between CREBH, the circadian transcriptional activators PPARα and C/EBPβ, and the repressor E4BP4 in the liver. ......................... 65 Figure 24. Illustration of CREBH working model as a circadian metabolic oscillator. .... 67 Figure 25. Tissue-specific expression of the mouse CrebH mRNA. .............................
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