Epigenetic resetting in the mammalian germline towards totipotency
Supervisor:Prof. Azim Surani
Second Supervisor: Prof. Julie Ahringer
Second Supervisors DepartmentGurdon Institute
Web Page: https://www.gurdon.cam.ac.uk
The key regulators of human primordial germ cells (hPGCs) specification are now known to be SOX17 and BLIMP1, which will be the basis for detailed future investigations. The aims are to determine the impact of gene dosage and the role key regulators as pioneer factor (s). Analysis of what constitutes the competent state for hPGC fate will also be addressed, which may reveal a definable transcriptional-epigenetic state that precedes gastrulation. Genetic and high-resolution imaging approaches, as well as single-cell analysis are available to address these and other questions using validated robust in vitro models with human pluripotent stem cells (hESC). hPGC specification is intimately linked with the initiation of epigenetic resetting, including extensive histone modifications, erasure of DNA methylation. These epigenetic changes are critical for the establishment of the totipotent state at fertilisation. The ultimate aim is to reconstitute the human germline cycle in vitro, which is necessary for detailed mechanistic studies of the human germ cell lineage.
Epimutations contribute to human somatic diseases, but these are apparently erased in the ‘immortal’ germline, which will inform advances in age related diseases. This work is also relevant to understand the causes on infertility and germ cell tumours.