PROJECT I The overarching hypothesis that we will test with this proposal is that human female infertility and assisted reproductive technology (ART) failures are, in part, caused by a disruption of the maternal mRNA translational program. Using a genome-wide strategy, we have assembled a blueprint of the translational regulations active during mouse oocyte maturation. We demonstrated that a large number of mRNAs coding for cell cycle components and for components of the transcriptional and chromatin remodeling machinery are translated following a well defined succession early during oocyte maturation. These findings have led to the hypothesis that timed translation of a subset of maternal mRNAs is critical for the oocyte to develop as an embryo. Moreover, we propose that somatic cell signals control this translational program of the oocyte. On the basis of preliminary data showing that the EGF-network plays a role in these somatic-germ cell interactions, we will explore how these signals contribute to developmental competence. The experimental plan is organized along three specific aims. With the first Aim, the oocyte translation program will be characterized in in vivo genetic models of compromised competence or after in vitro maturation. In the second Aim, the mechanisms by which somatic cells regulate translation in the oocytes will be investigated using in vitro models where somatic germ cell interactions are maintained and with reporters monitoring translation of candidate transcripts.
The third Aim will focus on translation of mRNAs coding for oocyte secretory products to predict actual protein secretion. These measurements will be used as a readout of correct execution of the translational program. Secretion from human oocytes will be used for proof of principle that these patterns reflect the competence of the oocyte to sustain embryo development. The concepts developed with this project will open new avenues for monitoring oocyte quality in assisted reproduction in clinical practice.

Public Health Relevance

With this proposal we will study the mechanisms involved in oocyte developmental competence Understanding this process at the molecular level will provide new tools and open new strategies to diagnose the origin of infertility and improve treatments of this condition. It will also provide new biomarkers useful to predict oocyte quality during in vitro fertilization.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD055764-07
Application #
8435286
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$308,929
Indirect Cost
$108,975
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Houshdaran, Sahar; Zelenko, Zara; Irwin, Juan C et al. (2014) Human endometrial DNA methylome is cycle-dependent and is associated with gene expression regulation. Mol Endocrinol 28:1118-35
Chen, Joseph C; Johnson, Brittni A; Erikson, David W et al. (2014) Seminal plasma induces global transcriptomic changes associated with cell migration, proliferation and viability in endometrial epithelial cells and stromal fibroblasts. Hum Reprod 29:1255-70
Lin, Chih-Jen; Koh, Fong Ming; Wong, Priscilla et al. (2014) Hira-mediated H3.3 incorporation is required for DNA replication and ribosomal RNA transcription in the mouse zygote. Dev Cell 30:268-79
Romero, Roberto; Dey, Sudhansu K; Fisher, Susan J (2014) Preterm labor: one syndrome, many causes. Science 345:760-5
Piltonen, T T; Chen, J; Erikson, D W et al. (2013) Mesenchymal stem/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display inflammatory and oncogenic potential. J Clin Endocrinol Metab 98:3765-75
Judson, Robert L; Greve, Tobias S; Parchem, Ronald J et al. (2013) MicroRNA-based discovery of barriers to dedifferentiation of fibroblasts to pluripotent stem cells. Nat Struct Mol Biol 20:1227-35
Afshar, Yalda; Hastings, Julie; Roqueiro, Damian et al. (2013) Changes in eutopic endometrial gene expression during the progression of experimental endometriosis in the baboon, Papio anubis. Biol Reprod 88:44
Lin, Chih-Jen; Conti, Marco; Ramalho-Santos, Miguel (2013) Histone variant H3.3 maintains a decondensed chromatin state essential for mouse preimplantation development. Development 140:3624-34
Chen, Li; Faire, Mehlika; Kissner, Michael D et al. (2013) Primordial germ cells and gastrointestinal stromal tumors respond distinctly to a cKit overactivating allele. Hum Mol Genet 22:313-27
Sachs, Michael; Onodera, Courtney; Blaschke, Kathryn et al. (2013) Bivalent chromatin marks developmental regulatory genes in the mouse embryonic germline inýývivo. Cell Rep 3:1777-84

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