UC San Diego

The earliest stages of life, including the transition from the fully differentiated oocyte to the totipotent zygote, the first days of embryo cleavage and cell differentiation to form a blastocyst, and implantation of that blastocyst in the wall of the uterus, are somehow beautifully simple and strikingly complex at the same time. These stages, which represent the beginning of life for us and other vertebrates, are difficult to study, owing to a number of experimental and ethical considerations. However, advances in our understanding of nuclear reprogramming, transcriptional quiescence and activation, the maintenance of pluripotency, and what it takes for an embryo to initiate contact with the endometrium to generate a successful pregnancy, will without question have far-reaching influence for many scientific and medical disciplines. Here, I attempt to unravel some of these concepts, combining molecular and developmental biology with genome-wide analysis only recently made possible through advances in techniques with low input. These approaches, in combination, allow us to ask questions about early developmental systems that would not have been possible only years prior.

In the oocyte, global transcriptional silencing is a highly conserved mechanism that is essential for the transition from the differentiated oocyte to the totipotent zygote. Here, I report that global transcriptional silencing in the mouse oocyte depends on an mRNA decay activator. By downregulating master regulators of transcription during oocyte growth, particularly a group of mRNAs encoding demethylases for H3K4 and H3K9, ZFP36L2 enables increased histone methylation that is associated with transcriptional silencing. These results uncover a mRNA decay mechanism that acts a developmental switch during growth of the mammalian oocyte, resulting in wide-spread shifts in chromatin modification, and mediating silencing of transcription in the oocyte.

The pluripotent population of cells in the blastocyst, the inner cell mass, is established in the mouse embryo approximately three days after fertilization. These cells will undergo gastrulation to form the entire organism and can be maintained in culture as embryonic stem cells. I report here that UPF2, a mRNA decay activator, is needed specifically within the pluripotent inner cell mass of the mouse embryo for maintenance of pluripotency in the embryo in vivo, as well as for embryonic stem cells in vitro. That mRNA decay may underly the establishment or maintenance of this intriguing and complex population of cells, is an exciting possibility.

Reproductive success depends on embryo implantation in the uterus, and in fertile and infertile couples alike, failure of the embryo to implant in the wall of the uterus accounts for up to 75% of all lost pregnancies. Here, I provide a qualitative assessment of gene expression and cellular communication networks within the major compartments of the human blastocyst that are most closely associated with successful implantation and ongoing pregnancy. Most strikingly, establishment and/or maintenance of the extraembryonic primitive endoderm lineage—following the second major embryonic differentiation event—most strongly differentiates embryos of high and low implantation potential. Unbiased machine learning identified genes within each embryo compartment most closely associated with implantation. Taken together, this data supports a model in which successful implantation and ongoing pregnancy predominantly depends upon the inner cell mass and highlights a potentially novel role for the extraembryonic primitive endoderm in early pregnancy success.