Did you know that the earliest stages of life — from worms to humans — occur in the absence of transcription? Our lab is working to understand the gene regulatory mechanisms that orchestrate these early developmental events. Below are examples of the types of questions we are working to answer in the laboratory.
To address these questions, we are integrating cutting-edge approaches in RNA, epigenetics, chromatin, and computational biology. And we are investigating these questions in mammals, using oocyte, embryo and stem-cell based models for the mouse and human.
Gene regulatory mechanisms driving development from oocyte to embryo
The transition from a fully differentiated oocyte to a totipotent embryo is arguably one of the most dynamic transitions in all of biology. As mentioned above, this transition from oocyte to embryo occurs in the absence of new transcription. Transcription is globally silenced in the oocyte before ovulation, and reactivation of transcription from the new embryonic genome does not fully resume until the late 2-cell embryo stage in mice and even later at the 4 to 8-cell stage in humans. Many developmental events essential for the earliest stages of life occur during this period of transcriptional silence, including oocyte maturation, fertilization, wide-spread epigenetic and chromatin structural changes, the first mitotic cell division(s), and finally, reactivation of transcription in the newly formed embryo. Without transcription, control of gene expression to drive these critical steps relies on post-transcriptional processes unique to the oocyte and embryo. How this complex gene regulation is orchestrated and how each of these developmental transitions are accomplished in the absence of transcription are major questions we are working to address.
Reprogramming the fully differentiated oocyte to the totipotent embryo
Stem cell reprogramming holds enormous potential for the study and treatment of disease. However, while many exciting advances have been made, cell reprogramming in vitro remains inefficient, and this inefficiency is a major limitation in the field. In contrast, reprogramming of a fertilized egg to a totipotent (not just pluripotent) embryo is highly efficient. And this efficiency is essential for life from worms to humans. Therefore, another important goal in the lab is to dissect the mechanisms required for efficient nuclear and cytoplasmic reprogramming across the transition from oocyte to embryo and to apply the insights learned to improve stem cell reprogramming in vitro.
Uncovering the molecular determinants of successful implantation of the human blastocyst
We, as humans, are remarkably inefficient at reproducing ourselves compared to other animals. The reasons for this remain poorly understood; however, high rates of molecular or genetic defects in human embryos leading high rates of implantation failure are thought to be a major contributor. In fact, early implantation failure is estimated to account for ~70% of lost pregnancies and is widely considered to be one of the greatest obstacles in treating infertility. Advances in the field have been limited for decades as the factors and pathways important for implantation in humans largely remain a black box. We are working to identify these factors and pathways critical for successful implantation of the human blastocyst and to develop stem-cell based models to dissect the underlying molecular mechanisms required. We hope these studies will provide much needed insight into the earliest stages of our own development and to improve implantation success in the IVF clinic.