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.
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:
- Why is a dampened ATM dependent DDR found in early cleavage stage embryos?
- Does an ATR mediated DDR play a role in embryonic reprogramming and totipotency emergence?
- 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
Startdatum | 1-6-2025 |
Einddatum | 31-5-2030 |
Subsidiejaar | 2025 |
Partners & Locaties
Projectpartners
- AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICASpenvoerder
Land(en)
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This project aims to elucidate the interplay between 3D genome organization and transcriptome dynamics in early mouse embryos to identify factors influencing cell fate decisions.
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This project aims to develop novel transgenic mouse models and technologies to study epigenome propagation during germline development, focusing on the role of hypomethylation in cell identity and stability.
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This project aims to integrate multi-scale dynamics of gene regulation during mammalian embryogenesis using advanced imaging and modeling techniques to enhance understanding of chromatin organization and transcriptional activity.
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This project aims to uncover how metabolic changes influence epigenetic outcomes during mouse embryo implantation, using multi-omic approaches and mechanistic experiments to explore regulatory processes.
Mechanisms and biological functions of H3K27me3 reprogramming in plant microspores
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