Pluripotency-specific regulation of transposable elements in mammalian development

important to understand the factors contributing to healthy embryo development. Furthermore, developmental pathways important for maintaining an undifferentiated state are often hijacked in diseases such as cancer.

The Chromatin and Development (Percharde) lab at the MRC LMS studies the transcriptional and epigenetic reprogramming events that take place in normal embryo development. We particularly focus on chromatin regulation and how this intersects with the regulation of transposable elements (TEs), which are mobile parts of our genome that have been greatly understudied. TEs are often associated with pathology, being able to cause DNA damage, inflammation, or mutagenesis when activated in somatic cells or cancer cells (1). However, we have intriguingly found evidence that these transposons are also expressed in normal development (2,3), without triggering immune activation or retrotransposition (4). We have also uncovered new chromatin-based mechanisms by which TEs are regulated in ESCs and embryos (5). Critically, the mechanisms that permit TE function and co-option whilst avoiding deleterious effects are largely unknown.

In this PhD, the student will investigate the unique relationship between TE activation, immune sensing and cell fate in early mammalian development. They will follow up on pathways that we believe to be important in this relationship, and may develop new approaches to explore the links between TE expression and TE sensing. The PhD candidate will be able to use a range of mouse/human embryonic stem cell lines and/or mouse embryology in their project to explore the relationship between chromatin and TE regulation across distinct embryonic and extra-embryonic lineages. They may employ a combination of candidate and genome-wide approaches, recent technologies such as spatial transcriptomics, CRISPRi/a, AI-based screening and bioinformatics to investigate novel aspects of TE regulation in development. They will be co-supervised by Dr Veronique Azuara, an expert in early mammalian development, cell fate, metabolism and epigenetics.

To apply for this project please follow the application instructions provided on the LMS website (https://lms.mrc.ac.uk/work-and-study/studentships/lms-4-year-phd-studentships/) and submit an application form by the deadline. 'Registering your interest' below will not be considered an application.

Funding Notes

This studentship covers all tuition fees as well as a tax free stipend amounting to £26,500pa paid directly to the student in monthly instalments.

The funding is available for both Home and Overseas students.

References

1. What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation. BIOESSAYS Percharde M, Sultana S and Ramalho-Santos M (2020) https://doi.org/10.1002/bies.201900232
2. CRISPRa-mediated disentanglement of the Dux-MERVL axis in the 2C-like state, totipotency, and cell death. SCIENCE ADVANCES Chammas P, Xie SQ, Sepulveda-Rincon L, Leeke BJ, Dore MH, Wagner RT, Chang N, Jones PL, McManus MT, Karimi M, Young G and Percharde M (2025) https://doi.org/10.1126/sciadv.adu9092
3. A LINE1-Nucleolin partnership regulates early development and ESC identity. CELL Percharde M, Lin CJ, Yin Y, Guan J, Peixoto GA, Bulut-Karslioglu A, Biechele S, Huang B, Shen X and Ramalho-Santos M (2018) https://doi.org/10.1016/j.cell.2018.05.043
4. Inhibition of cytosolic DNA sensing and transposon activity safeguards pluripotency (Preprint) BIORXIV Garcia-Llagostera F, Putman ALK, Choromidis A, Leeke BJ, Stanik K, Ramos-Guzman A, Moyon B, Gil J, Barr AR & Percharde M (2025) https://doi.org/10.1101/2025.03.26.645264
5. Nucleolar-based Dux repression is essential for embryonic two-cell stage exit. GENES AND DEVELOPMENT Xie SQ, Leeke BJ, Whilding C, Wagner RT, Garcia-Llagostera F, Low XY, Chammas P, Cheung NT-F, Dormann D, McManus MT, Percharde M. (2022) https://doi.org/10.1101/gad.349172.121