The long-term goal of this application is to determine underlying mechanisms that govern changes in gene expression during oocyte growth and the maternal-to-zygotic transition, both of which are linked and essential for development. A universal feature of oocyte development is that transcription declines commencing around mid-growth such that fully-grown oocytes are essentially transcriptionally quiescent. In mouse, this decline correlates with visible changes in chromatin structure, which becomes more condensed and decreased activity of the transcription machinery. Using a transgenic RNAi approach that permits study of the function of any gene in oocyte development, Specific Aim 1 will test the hypothesis that members of the HP1 family of chromatin-binding proteins and UBC9, via its central role in sumoylation, are essential for changes in chromatin structure and transcriptional activity that occur during oocyte growth. A major reprogramming of gene expression is first detected during the 2-cell stage and essential for continued development. Superimposed on genome activation is development of a chromatin-mediated transcriptionally repressive state. Our transcript profiling experiments identified Myc as a candidate gene pivotal for genome activation and reprogramming of gene expression, and Hdad as essential for establishing the transcriptionally repressive state. Using an RNAi approach to target Myc and Hdad, Specific Aim 2 will test the hypothesis that Myc and Hdad are critical for these two processes that collaboratively sculpt the appropriate pattern of gene expression required for successful development following genome activation. Oocytes express miRNAs and mRNA degradation, which initiates during oocyte maturation and continues during early preimplantation development, is a post-transcriptional mechanism that contributes to determining the global pattern of gene expression in the embryo.
Specific Aim 3 will test the hypothesis that miRNAs target specific mRNAs for degradation in P-bodies and that this mechanism is essential for proper oocyte/embryo development. The proposed studies will increase our basic knowledge and understanding of human development. In the near term, they may help improve treatment of human infertility by providing new knowledge that will facilitate the rational development of treatments that foster improved oocyte and preimplantation embryo development in the practice of Assisted Reproductive Technology (ART).
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|Ma, P; Schultz, R M (2016) HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation. Cell Death Differ 23:1119-27|
|Svoboda, Petr; Franke, Vedran; Schultz, Richard M (2015) Sculpting the Transcriptome During the Oocyte-to-Embryo Transition in Mouse. Curr Top Dev Biol 113:305-49|
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|Stein, Paula; Rozhkov, Nikolay V; Li, Fan et al. (2015) Essential Role for endogenous siRNAs during meiosis in mouse oocytes. PLoS Genet 11:e1005013|
|Jimenez, Richard; Melo, Eduardo O; Davydenko, Olga et al. (2015) Maternal SIN3A regulates reprogramming of gene expression during mouse preimplantation development. Biol Reprod 93:89|
|Abe, Ken-Ichiro; Yamamoto, Ryoma; Franke, Vedran et al. (2015) The first murine zygotic transcription is promiscuous and uncoupled from splicing and 3' processing. EMBO J 34:1523-37|
|Ma, Pengpeng; de Waal, Eric; Weaver, Jamie R et al. (2015) A DNMT3A2-HDAC2 Complex Is Essential for Genomic Imprinting and Genome Integrity in Mouse Oocytes. Cell Rep 13:1552-60|
|Ma, Jun; Fukuda, Yusuke; Schultz, Richard M (2015) Mobilization of Dormant Cnot7 mRNA Promotes Deadenylation of Maternal Transcripts During Mouse Oocyte Maturation. Biol Reprod 93:48|
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