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

This project aims to investigate the roles of DNA damage response pathways and splicing failures in early mouse embryo development and totipotency through a multidisciplinary approach.

Subsidie
€ 1.993.143
2025

Projectdetails

Introduction

In mammals, oocyte fertilisation is followed by a dramatic epigenetic and transcriptomic reprogramming 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.

ATM and ATR Kinase Activity

Despite this, work by ourselves and others suggests that 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 reprogramming, as DNA damage acting through this pathway can reprogram embryonic stem cells to a more totipotent state reminiscent of the early post-fertilisation embryo.

Programmed Splicing Failure

Beyond this, little is known about DDRs in the early embryo. However, we have recently identified a programmed splicing failure that accompanies the transcriptomic reprogramming 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.

Fundamental Questions

These findings raise three fundamental questions:

  1. Why is a dampened ATM dependent DDR found in early cleavage stage embryos?
  2. Does an ATR mediated DDR play a role in embryonic reprogramming and totipotency emergence?
  3. What is the impact of the programmed splicing failure on embryo development and totipotency, and is it related to DDR regulation?

Research Approach

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.

Financiële details & Tijdlijn

Financiële details

Subsidiebedrag€ 1.993.143
Totale projectbegroting€ 1.993.143

Tijdlijn

Startdatum1-6-2025
Einddatum31-5-2030
Subsidiejaar2025

Partners & Locaties

Projectpartners

  • AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICASpenvoerder

Land(en)

Spain

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