Regulation of Polycomb by long noncoding RNAs during pre-implantation development

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ABSTRACT Polycomb Repressive Complex 2 (PRC2) is a multi-subunit enzyme that is essential for preimplantation development and the subsequent development of every major embryonic lineage. PRC2 represses gene expression, yet the mechanisms of its recruitment to specific genomic regions for gene repression remain poorly understood. PRC2 is known to be recruited to specific genomic regions by repressive long non-coding RNAs (lncRNAs), such as Xist, but it is unclear how lncRNAs like recruit PRC2 and cause it to repress genes so effectively. I identified the RNA-binding protein (RBP) scaffold attachment factor B1 (SAFB1) as a PRC2 interactor and is important for PRC2 mediated gene silencing. Moreover, prior studies have shown that SAFB1 is essential for development and plays an important role during cellular stress. My proposal will determine the physical mechanism of interaction between SAFB1, PRC2, and Xist, whether RNA is the basis of SAFB1/PRC2 specific interactions, and finally, the extent to which SAFB1 regulates PRC2 and the roles this interaction plays during stress in preimplantation development. The objective of the proposed project is to determine how PRC2 is regulated by repressive lncRNAs in preimplantation development and if successful, will identify a new pathway that regulates stress in the developing embryo and will provide insight as to how PRC2 is recruited and regulated by lncRNAs. In time, these experiments can provide a foundation for approaches to control PRC2 therapeutically, as a means to correct structural birth defects, and to improve methods for in vitro fertilization. My long-term goal is to become an independent scientist at an academic institution where I can perform research at the intersection of epigenetics and development. The University of North Carolina at Chapel Hill, and the Department of Pharmacology in which my sponsor’s lab is housed, is an extremely collaborative and supportive environment to receive training in the skills I need to attain my goal. First, during the fellowship award period, I plan receive extensive training in experimental techniques such as genomics, computational biology, stem cell biology, and developmental epigenetics, through guidance from my sponsor and co-sponsor, as well as through classes and a Cold Spring Harbor Laboratories mouse course. Second, I plan to develop skills that will allow me to gain scientific independence. I will attend meetings and learn to critically review literature. Third, I will learn to clearly and effectively communicate my science, written and orally, through publishing at least one first authored publication and review by the end of my fellowship period, and by presenting my research at various public forums. Lastly, I will gain skills in mentorship and leadership through participation in career workshops tailored for academic research careers and science education. Therefore, my training under this award will result in the development of crucial skills needed for me to achieve my long-term goal.