Gene regulatory mechanisms driving development during transcriptional silence from oocyte to embryo in mammals

University Of California, San Diego, La Jolla CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT The transition from a fully differentiated oocyte to a totipotent embryo is one of the most dynamic transitions in biology. Remarkably, this transition occurs in the absence of new transcription. In the mouse, transcription is globally silenced in the oocyte before ovulation and is not fully reactivated until the late 2 cell embryo stage. This period of transcriptional quiescence is highly conserved from worms to humans, and oocytes that fail to undergo transcriptional silencing are not fully competent to support further development. Without new transcription, the oocyte and early embryo depend upon post-transcriptional mechanisms to regulate gene expression to drive development through this window of transcriptional silence. However, the mechanisms required to silence transcription in the oocyte and orchestrate gene expression in the absence of transcription during development remain poorly understood, particularly in mammals. A better understanding of these mechanisms is critical both to improve our understanding of the earliest stages of mammalian development and the diagnosis and treatment of infertility, as only ~50% of in vitro fertilized human embryos successfully traverse this period of transcriptional silence. The overarching goal of this project is to uncover molecular mechanisms required for successful developmental progression from oocyte to embryo during this window of transcriptional silence. One post-transcriptional mechanism known to play a critical role during this period is regulation of mRNA polyadenosine (poly(A)) tail length in the cytoplasm to control translation, where cytoplasmic polyadenylation activates translation and deadenylation leads to translational repression and/or decay. In recent findings from our laboratory, we have profiled poly(A) tail lengths transcriptome-wide across the entire transition from oocyte to embryo. Integrating these data with recently published ribosome profiling data, we have produced the first transcriptome- wide analysis of poly(A) tail and translation dynamics across the entire oocyte-to-embryo transition in a mammalian system. Building on these data, we plan to use the mouse model to investigate (i) the mechanisms that drive global transcriptional silencing in the oocyte; (ii) the post- transcriptional mechanisms regulating poly(A) tail length and gene expression during transcriptional silence; and (iii) regulation of maternal factors required to mediate reprogramming to totipotency. These studies will advance our understanding of the mechanisms that drive gene expression and development during transcriptional silence from oocyte to embryo in mammals, with the long-term potential to improve the diagnosis and treatment of infertility.