The germ cell lineage gives rise to the gametes, which ensures the transmission of genetic and epigenetic information to the subsequent generation. In mice, the foundation of the germ cell lineage is based on the specification of primordial germ cells (PGCs) during embryonic development. Following specification, PGCs are epigenetically reprogrammed by active DNA demethylation and chromatin remodelling resetting the epigenome for acquiring totipotency. However, the underlying mechanisms of PGC reprogramming are not well understood. Recent studies point towards a role for the histone variant H3.3 as a central mediator of epigenetic reprogramming of PGCs. Most notably, the histone chaperone HIRA, which is necessary for the deposition of H3.3 into nucleosomes, is highly enriched in nascent PGCs. The proposed study aims to elucidate mechanisms of epigenetic reprogramming and its role in the establishment of the pluripotent state. Therefore, I aim to study the role of the key histone variant H3.3 and its regulation by the histone chaperone HIRA in PGCs by generating knockout mice models. Further, to gain new insight into the establishment of the unique chromatin signature in PGCs, I will monitor fluorescently labelled H3.3 in PGCs by time-lapse confocal microscopy. This will not only provide significant insight into the nucleosome dynamics of H3.3 but will also for the first time capture epigenetic reprogramming of PGCs in real-time.
During my postdoctoral studies I will not only expand my background in cell fate specification and epigenetics in C. elegans and Drosophila towards a vertebrate model but will also establish novel in vivo imaging techniques in an excellent scientific environment. This project provides training in techniques of germ cell and stem cell biology and offers the opportunity to establish collaborations, altogether putting me in an excellent position for my future career as an independent researcher.
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