Self-sabotage in the early mammalian embryo: investigating the interplay between DNA damage responses, splicing failure and zygotic reprogramming

In mammals, oocyte fertilisation is followed by a dramatic epigenetic and transcriptomic reprograming to prepare the newly formed embryo for subsequent development.

Preserving genome integrity is critical at these early stages, when all cells have the potential to contribute to a large proportion of the embryo including the germ line.

Despite this work by ourselves and others suggests the ATM kinase driven DNA damage response (DDR) to double strand breaks is dampened in the early embryo.

At the same time the ATR kinase mediated DDR appears fully active and may even function in zygotic reprograming, as DNA damage acting through this pathway can reprogram embryonic stem cells to a more totipotent state reminiscent of the early post-fertilisation embryo.

Beyond this little is known about DDRs in the early embryo, however we have recently identified a programmed splicing failure that accompanies the transcriptomic reprograming of the embryo and disproportionately disrupts transcripts coding for DDR genes.

Furthermore, splicing inhibition has been found to reprogram embryonic stem cells to a more totipotent state and we have found this also inordinately disrupts DDR gene transcripts.

These findings raise three fundamental questions: i) Why is a dampened ATM dependent DDR found in early cleavage stage embryos?ii) Does an ATR mediated DDR play a role in embryonic reprograming and totipotency emergence?iii) What is the impact of the programmed splicing failure on embryo development and totipotency, and is it related to DDR regulation?We will take a multidisciplinary approach to answer these questions using a combination of high-throughput -omics and focused techniques in the early mouse embryo.

The knowledge gained will represent a breakthrough in the understanding of early mammalian post-fertilisation development, allowing us to unravel the interaction between the unique cellular processes that occur at this time, genome integrity control and splicing failure.