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Eastern Illinois University The Keep Masters Theses Student Theses & Publications 2017 The Role of CREG1 as a Master Regulator of Liver Function Abdulrahman Siran Aldaghmi Eastern Illinois University This research is a product of the graduate program in Biological Sciences at Eastern Illinois University. Find out more about the program. Recommended Citation Aldaghmi, Abdulrahman Siran, "The Role of CREG1 as a Master Regulator of Liver Function" (2017). Masters Theses. 2719. https://thekeep.eiu.edu/theses/2719 This is brought to you for free and open access by the Student Theses & Publications at The Keep. It has been accepted for inclusion in Masters Theses by an authorized administrator of The Keep. For more information, please contact [email protected]. The Graduate School� EASTERN ILuNOrsUN1vERsrrr Thesis Maintenance and Reproduction Certificate FOR: Graduate Candidates Completing Theses in Partial Fulfillment of the Degree Graduate Faculty Advisors Directing the Theses RE: Preservation, Reproduction, and Distribution of Thesis Research Preserving, reproducing, and distributing thesis research is an important part of Booth Library's responsibility to provide access to scholarship. In order to further this goal, Booth Library makes all graduate theses completed as part of a degree program at Eastern Illinois University available for personal study, research, and other not-for-profit educational purposes. Under 17 U.S.C. § 108, the library may reproduce and distribute a copy without infringing on copyright; however, professional courtesy dictates that permission be requested from the author before doing so. Your signatures affirm the following: • The graduate candidate is the author of this thesis. • The graduate candidate retains the copyright and intellectual property rights associated with the original research, creative activity, and intellectual or artistic content of the thesis. • The graduate candidate certifies her/his compliance with federal copyright law (Title 17 of the U. S. Code) and her/his right to authorize reproduction and distribution of all copyrighted materials included in this thesis. • The graduate candidate in consultation with the faculty advisor grants Booth Library the non­ exclusive, perpetual right to make copies of the thesis freely and publicly available without restriction, by means of any current or successive technology, including by not limited to photocopying, microfilm, digitization, or internet. • The graduate candidate acknowledges that by depositing her/his thesis with Booth Library, her/his work is available for viewing by the public and may be borrowed through the library's circulation and interlibrary loan departments, or accessed electronically. • The graduate candidate waives the confidentiality provisions of the Family Educational Rights and Privacy Act (FERP A) (20 U. S. C. § 1232g; 34 CFR Part 99) with respect to the contents of the thesis and with respect to information concerning authorship theof thesis, including name and status as a student at Eastern Illinois University. I have conferred with my graduate faculty advisor. My signature below indicates that I have read and agree with the above statements, and hereby give my permission to allow Booth Library to reproduce and distribute my thesis. My adviser's signature indicates concurrence to reproduce and distribute the thesis. Graduate Candidate Signature Faculty Advi¢'Signature Printed Name Printed Name Date Please submit in duplicate. THE ROLE OF CREG1 AS MASTER REGULATOR OF LIVER FUNCTION (TITLE) BY ABDULRAHMAN SIRAN ALDAGHMI THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science IN THE GRADUATE SCHOOL, EASTERN ILLINOIS UNIVERSITY CHARLESTON, ILLINOIS 2017 YEAR I HEREBY RECOMMEND THAT THIS THESIS BE ACCEPTED AS FULFILLING THIS PART OF THE GRADUATE DEGREE CITED ABOVE .7/7//11 �I..f/W/Y �r· THESIS CO�ITTEE CHAIR DATE DEPARTME�]SCHOOLCHAIR DATE OR CHAIR'S DESIGNEE �8'/1r THESIS COMMITTEE MEMBER DATE THESIS COMMITTEE MEMBER DATE SLrtf 'J-0\ I THESIS COMMITTEE MEMBER DATE THESIS COMMITTEE MEMBER DATE The Role of CREG 1 as a Master Regulator of Liver Function Abdulrahman Aldaghmi Department of Biological Sciences Eastern Illinois University Charleston, IL-61920 © 201 7 by Abdulrahman Aldaghmi ii COMMITTEE IN CHARGE OF CANDIDACY Professor Dr. Gary A. Bulla, Advisor Professor Dr. Britto P. Nathan Instructor Dr. Antony 0. Oluoch iii ABSTRACT The liver is known as the chemical factory of the body because it performs a wide range of biochemical functions required for life. Since the liver has such an important role in regulation of normal physiological processes, liver diseases cause a high rate of morbid ity and mortality. Therefore, understanding the mechanisms of liver development will shed light on the causes of liver disease. In this study, a cell line model that utilizes rat hepatoma cells (Fg14) and hepatoma variant cells (Hll) was used to identify master regul ators of liver gene expression. Whole genome expression studies identified the gene CREGl (Cellular repressor of ElA-stimulated genes-1) as a potential master regulator of liver gene expression. The ability of CREGl to restore liver gene expression in the Hll variant cell line was determined by forced overexpression of this gene via transfection of Hll cells with a CREGl expression vector. Rescue of the liver-specific gene SERPINAl (which produces a protein that plays a role in regulatory functions in the inflammatory, complement, coagulation, and fibrinolytic cascades and whose expression is used as a marker for liver function) was tested using RT-PCR. Results show that SERPINAl gene expression was fully rescued. Importantly, genes encoding liver-specific transcription factors were also rescued, including Hepatocyte Nuclear Factors HNFla and HNF4. In subsequent experiments, it was found that CREGl expression also activated several additional genes located in the SERPIN locus which have been suggested to be controlled by the SERPIN Locus Control Region (LCR). This was surprising considering most serpin genes have not been shown to be activated by the HNF4/HNF1 pathway. Because HNF6 (Onecut) has been previously shown to bind to the serpin LCR, we measured its expression and found it to be rescued as well with CREGl overexpression. We next asked whether HNF6 alone could rescue serpin locus gene expression by transfecting Hll cells with an HNF6 expression vector. The H11- HNF6 cells showed rescue of many of the serpin locus genes, although only partial rescue was observed. Likewise, a partial rescue of HNF4 and HNFl genes was observed in the H11-HNF6 cells, but not to the level observed in the H11-CREG1 cells. We conclud e that CREGl can fully rescue expression of several liver-specific genes, including transactivation genes, suggesting its role as a master regulator of liver function. CREGl action appears to act at least partially through HNF6 gene activation as well as through activation of the HNF4/HNF1 pathway, both of which act to increase expression of the serpin locus through both LCR activation (through HNF6) and individual serpin gene activation (through HNF4/HNF1). iv Dedicated to Fandia Alrowily and Siran Aldaghmi v Acknowledgments I would like to express the deepest appreciation to everyone who helped and encouraged me until completion of my Master's thesis project. Without their support and assistance this work would not have been possible. I would like to acknowledge those who gave me deep insight and expertise that also extremely assisted the project. I submit my heartiest gratitude to my respected advisor Dr. Gary A. Bulla, for his detailed instructions, advice, suggestion, support, and constructive criticism that led me to complete my thesis. He gave me worthy information in my research filed that would not have been easy to comprehend. I am thankful for keeping your office door always open for me and all students. It was a pleasure working as member in his lab crew. Actually, there are no words that sufficiently describe how thankful I am for your kindness. I would like to thank my committee members, Dr. Britto P. Nathan and Dr. Antony 0. Oluoch I am deeply grateful for your comments and suggestions. They were keen to give important advice to finish my research properly. It was a pleasure to stand in front of you and hear your guidance that helped me a lot in supporting my research. A very special thanks to my parents for their absolute encouragement, I could not reach what I want without their determination and persistence to achieve my goals. I would also like to express my gratitude to all of my family who urged me and put their faith in me to achieve my ambitions. I am deeply indebted to my brother Ahmed who did not go for higher stud ies due to his responsibilities to take care of my family. Last but not least, I would like to take this opportunity to record my sincere thanks to Al Jouf University for p roviding a full scholarship that fully supported me through tuition and living expenses. I am grateful to be one of its faculty members. Lastly, I am hugely indebted to Eastern Illinois University for giving me the opportunity to be a graduate student here and to fulfill my dreams. vi Table of contents Abstract....................... .............................................................................................. iv Acknowledgments ............................................................................................................ vi Table of contents .............................................................................................................vii
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