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Role of Maternal Sin3a in Reprogramming Gene Expression During Mouse Preimplantation Development

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Role of Maternal Sin3a in Reprogramming Gene Expression During Mouse Preimplantation Development University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Role Of Maternal Sin3a In Reprogramming Gene Expression During Mouse Preimplantation Development Richard A. Jimenez University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Developmental Biology Commons, and the Genetics Commons Recommended Citation Jimenez, Richard A., "Role Of Maternal Sin3a In Reprogramming Gene Expression During Mouse Preimplantation Development" (2016). Publicly Accessible Penn Dissertations. 2366. https://repository.upenn.edu/edissertations/2366 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2366 For more information, please contact [email protected]. Role Of Maternal Sin3a In Reprogramming Gene Expression During Mouse Preimplantation Development Abstract In mouse, the maternal-to-zygotic transition entails a dramatic reprogramming of gene expression during the course of zygotic genome activation, which is essential for continued development beyond the 2-cell stage. Superimposed on zygotic genome activation and reprogramming of gene expression is formation of a chromatin-mediated transcriptionally repressive state that promotes repression of genes at the 2-cell stage. Experimentally inducing global histone hyperacetylation relieves this repression and histone deacetylase 1 (HDAC1) is the major HDAC involved in the development of this transcriptionally repressive state. Because SIN3A is essential for mouse development and is part of a HDAC1/2-containing complex, I investigated the role of maternal SIN3A in the development of the global transcriptionally repressive state that develops during the course of genome activation and reprogramming. In addition, previous microarray data generated from our lab of oligo (dT) primed mouse oocyte and 1-cell embryo cDNA revealed an elevation in the relative abundance of the Sin3a transcript between the oocyte and 1-cell stages; the elevation in relative transcript abundance suggests that the Sin3a transcript undergoes translational recruitment during oocyte maturation because the elevation occurs during a period of transcriptional quiescence. Here I show that the Sin3a transcript is recruited for translation during oocyte maturation and following fertilization. I demonstrated that maternal SIN3A is essential for preimplantation development and the reprogramming of genes expression, because inhibiting the maturation-associated increase in SIN3A leads to an arrest in mouse embryonic development and unfaithful reprogramming of gene expression in 2-cell mouse embryos. The mid 1-cell embryo contains the maximum level of maternal SIN3A protein and the protein then rapidly decreases to essentially an undetectable level by the mid 2-cell stage; the rapid loss of maternal SIN3A is likely mediated by the proteasome because a proteasome inhibitor substantially inhibits the loss of maternal SIN3A. Due to the restricted presence of the maturation-associated increase in SIN3A, the function of maternal SIN3A is likely constrained to the 1-cell stage of mouse development. However, the increase in maternal SIN3A does not play a role in the minor ZGA, as depleting maternal SIN3A had no effect on global transcription in 1-cell embryos, but surprisingly results in histone hypoacetylation in 1-cell mouse embryos. Maintaining the presence of maternal SIN3A beyond the 1-cell stage had no effect on pre- and postimplantation development. Collectively, these findings indicate that the maturation-associated increase in SIN3A regulates the reprogramming of gene expression and the oocyte may utilize the translational recruitment of transcripts encoding chromatin-modifying-related factors during oocyte maturation as a post- transcriptional mechanism to faithfully execute the reprogramming of gene expression through the utilization of a maternally-derived transcription machinery. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Richard M. Schultz Keywords dormant maternal mRNA, maternal-to-zygotic transition, mouse preimplantation development, reprogramming, Sin3a, zygotic genome activation Subject Categories Developmental Biology | Genetics This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2366 ROLE OF MATERNAL SIN3A IN REPROGRAMMING GENE EXPRESSION DURING MOUSE PREIMPLANTATION DEVELOPMENT Richard A. Jiménez A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2016 Supervisor of Dissertation _____________________ Richard M. Schultz, Ph.D. Charles and William L. Day Distinguished Professor of Biology Graduate Group Chairperson _____________________ Daniel S. Kessler, Ph.D. Associate Professor of Cell and Developmental Biology Dissertation Committee Hua-Ying Fan, Ph.D., Assistant Professor of Biochemistry and Biophysics George L. Gerton, Ph.D., Research Professor of Reproductive Biology in Obstetrics and Gynecology Peter S. Klein, M.D., Ph.D., Professor of Medicine Christopher J. Lengner, Ph.D., Assistant Professor of Cell and Developmental Biology ACKNOWLEGMENTS I would first like to thank my mentor, Richard Schultz for his guidance, patience and intellect as all these qualities has kept me stimulated as a graduate student and has motivated me to continue my growth as a scientist and person. I am also tremendously grateful for connecting me to amazing researchers at the Smithsonian Conservation Biology Institute in Front Royal, Virginia. Several past and current members of the lab have provided invaluable advice, expertise and skills. I especially thank Eduardo Melo for helping me with the initial experiments and review of the literature when the project first began. Paula Stein has trained me on many of the methods used in this project and her tremendous patience and excellent proficiency was instrumental throughout my time in the Schulz lab. She also provided useful feedback on a number of scientific presentations and provided valuable intuition on politics, life and especially the World Cup. I especially thank Jun Ma, Sergey Medvedev, and Pengpeng Ma for providing technical advice and help throughout my graduate time in the lab. I would also like to thank several people who have shared their expertise and time throughout my graduate career. I thank Chris Lengner, Peter Klein, George Gerton and Hua-Ying Fan for their support, constructive criticism, and honesty on my project and for providing an “out-of the box” perspective. They also were very helpful in keeping me focused throughout my graduate career. I want to express my gratitude and acknowledge the VMD/PhD program. I particular want to thank Mike Atchison for his advice, and tremendous support over my veterinary and graduate studies! I also want to thank the Predoctoral Training Grant in Genetics for their financial support through my graduate studies. I particularly want to thank Meera Sundaram for her strong dedication and time to keep this valuable training grant running strong! I am also greatly indebted to my collaborators that I have been fortunate enough to work with on this project. Olga Davydenko in the Mainigi lab for conducting the overexpression experiments and embryo transfers. Jun Ma for ii processing the invaluable experimental samples for the microarray analysis. John Eppig for his guidance on the in vitro maturation and in vitro fertilization experiments that allowed the project to address questions that would have been impossible to tackle without his useful advise. Vedran Franke from the Kristian Vlahoviček lab for all of his time and proficiency in bio-informatics that help with our analysis of the microarray data. Finally, I would not be where I am today without the support, love and dedication from my family and friends, especially my mother and father, Vivian and Benito. They supported and natured me throughout my education from the time I was an adolescent, and this thesis would not have been achievable without their commitment to my achievement. I also want to thank my grandparents, who taught their grandchildren and children the virtues of hard work and endurance with their own life. My maternal grandmother, Toni Delgado, who unfortunately is not with us anymore, showed the importance of education and perseverance by going through great odds to complete her high school education while having non-supportive parents. iii ABSTRACT ROLE OF MATERNAL SIN3A IN REPROGRAMMING GENE EXPRESSION DURING MOUSE PREIMPLANTATION DEVELOPMENT Richard A. Jiménez Richard M. Schultz In mouse, the maternal-to-zygotic transition entails a dramatic reprogramming of gene expression during the course of zygotic genome activation, which is essential for continued development beyond the 2-cell stage. Superimposed on zygotic genome activation and reprogramming of gene expression is formation of a chromatin-mediated transcriptionally repressive state that promotes repression of genes at the 2-cell stage. Experimentally inducing global histone hyperacetylation relieves this repression and histone deacetylase 1 (HDAC1) is the major HDAC involved in the development of this transcriptionally repressive state. Because SIN3A is essential for mouse development and is part of a HDAC1/2-containing complex, I investigated the role of maternal SIN3A in the development of the global
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