How can a single differentiated cell, the newly fertilized egg, give rise to an organism with multiple complex tissues? We are interested in understanding the first critical steps of this process in mammals during which totipotency, the ability to give rise to all tissues of the developing embryo, is first gained and then rapidly lost. The emergence of totipotency involves a dramatic epigenetic, transcriptomic and metabolic reprogramming, which we are only beginning to understand, and occurs more or less concurrently with the transcriptional activation of the zygotic genome. Potency then gets gradually restricted, first with the specification of the mammal specific extraembryonic lineages, that will support embryo growth in utero, and later though the formation of the germline and three germ layers which will give rise to the fetus itself.
The processes that occur at the early stages of mammalian development, particularly zygotic genome activation and the cellular reprogramming that accompanies totipotency emergence likely put a large amount of genomic and cellular stress on the embryo. This is a time when preserving genome integrity is crucial as any cell has the potential to contribute to a large proportion of the embryo and the germ line. Indeed, both ourselves and others have previously shown that cell death and DNA damage responses are dynamically regulated prior to embryo lineage specification, and that this is influenced by multiple factors, including alterations in alternative splicing, microRNA regulation or mitochondrial dynamics.
In our lab we use mouse embryos and embryonic stem cells and a wide variety of experimental approaches; including genome editing, functional genomics, embryo micromanipulation and confocal imaging, to investigate how the mechanisms involved in the regulation of genome integrity and cell death are coordinated with early developmental processes, both to ensure embryo viability and fitness and to facilitate the acquisition of totipotency and cell fate determination.
Activation of the ATM DNA damage response (red) upon induction of DNA lesions is lower in 2 cell (left) than early morula (right) stage mouse embryos (Wyatt, Pernaute et al, 2022).