Proposal title Investigating the role of KDM4 demethylases on extraembryonic lineage competency in mice and humans
| Title | Proposal title Investigating the role of KDM4 demethylases on extraembryonic lineage competency in mice and humans |
|---|---|
| Acronym | KICK |
| Start date | 2025-05-15 |
| End date | 2027-05-16 |
| Sponsor | Marie Skłodowska-Curie Action (MSCA) |
| Institution | KU Leuven |
| Principal investigator | Wilhelm Bouchereau
E-Mail: wilhelm.bouchereau@kuleuven.be |
Associated cell lines
Project Description
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 (huESC) and derivatives can be used as models of embryonic counterparts and possess equivalent extraembryonic lineage competency. In addition, huESC 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.