UC San Diego

The oocyte-to-embryo transition is arguably one of the most dramatic transitions in biology. Remarkably, this entire transition takes place in the absence of de novo transcription. Transcription by RNA Polymerase II (RNAPII) is globally repressed in the growing oocyte (Global Transcriptional Silencing, GTS) and does not get fully reactivated until the 2-cell embryo stage in mice and 8-cell embryo stage in humans (Embryonic Genome Activation, EGA). Importantly, oocytes that fail to undergo GTS have significantly diminished developmental competence, with reduced rates of maturation, fertilization, and embryo development. Temporally linked to transcriptional silencing, oocytes undergo a DNA configuration change from non-surrounded nucleolus (NSN) to surrounded nucleolus (SN), where the DNA becomes condensed around the nucleolus. Like GTS, oocytes that fail to transition from NSN to SN configuration also have lower rates of fertilization and subsequent embryo development. While GTS and NSN-to-SN transition are critical for the oocyte-to-embryo transition, little is known about the mechanisms that facilitate them.

The goal of my dissertation research is to delineate the mechanisms through which the RNAPII activity is repressed in the growing oocyte as GTS is established and uncover the relationship between transcriptional silencing and global chromatin condensation that leads to the NSN-to-SN transition. In Chapter 1, I introduce and summarize the current state of knowledge on the oocyte-to-embryo transition, GTS, NSN-to-SN transition, regulation of RNAPII during GTS, and oocyte developmental competence. In Chapter 2, I present findings on the regulation of groups of genes critical for RNAPII transcription at the onset of GTS. In Chapter 3, I present evidence that manipulating abundance or activity of these key players in otherwise transcriptionally active oocytes leads to global silencing of transcription and chromatin condensation, thereby facilitating the NSN-to-SN transition, and explore the role of histone modifications in this process. In Chapter 4, I discuss these findings in the context of previous studies and suggest future research directions related to these results.