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Investigating the role of KDM4 demethylases on extraembryonic lineage competency in mice and humans

Project description

Epigenetic regulation of early human embryonic development

Epigenetic regulation plays a central role in guiding embryonic development by determining which genes are switched on or off at critical stages. During the first weeks, human embryos generate extraembryonic tissues essential for supporting growth. Impaired formation of these tissues can lead to pregnancy complications such as preterm birth. Unlike mice, human embryonic cells show prolonged plasticity, but the mechanisms remain poorly understood. With the support of the Marie Skłodowska-Curie Actions programme, the KICK project will investigate the role of KDM4 demethylases, enzymes that remove epigenetic barriers. Researchers will employ stem cell-based embryo models to reveal how epigenetic control shapes embryonic competency and contributes to pregnancy health.

Objective

During the first two weeks of human development, the embryo will generate sequentially progenitors of the extraembryonic membranes that will form the supportive tissues of the embryo proper. Impairments of their development have been linked to pregnancy diseases such as preterm birth. Human embryonic cells differ from mice by their remarkable plasticity, which allows them to generate extraembryonic lineages during a protracted period of time. The mechanism extending human embryonic cells competency remains a mystery.
Enzymes of the KDM4 family remove Histone 3 lysine 9 methylation, a major epigenetic barrier to lineage conversion. However, there is a dramatic lack of knowledge on the role of KDM4s during early embryonic development. In this project I will investigate the function of KDM4 demethylases and how they influence embryonic cell competency in humans and mice. Human embryonic stem cells (hESC) and derivatives can be used as models of embryonic counterparts and possess equivalent extraembryonic lineage competency. In addition, hESC can be made to self-assemble into more complex 3D embryo models. These models provide an exciting and more accessible alternative to human embryos.
In this project, I will leverage the combined expertises of the host lab and myself in embryology and stem cell based models to chart for the first time the localization of KDM4 demethylases and perturbate their expression with cutting edge CRISPR-dCAS9 technologies in models of human early development. Both myself and the host’s previous works have shown that the manipulation of chromatin regulators can be harnessed to break epigenetic barriers. I will thus use the overexpression of KDM4 demethylases to also enhance mouse embryonic cells competency. Elucidating how human embryonic cells retain extraembryonic plasticity compared to mice will be key to further our knowledge of the specificities of human early development and better understand and model pregnancy disorders.

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Programme(s)

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Topic(s)

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Funding Scheme

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

KATHOLIEKE UNIVERSITEIT LEUVEN
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 200 400,00
Address
OUDE MARKT 13
3000 LEUVEN
Belgium

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Region
Vlaams Gewest Prov. Vlaams-Brabant Arr. Leuven
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

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