Global rewiring of genome organisation during transition to gametogenesis in gonadal germ cells
Global epigenetic resetting in the gonadal primordial germ cells (PGCs) enables transition to gametogenesis and eventual restoring of totipotency after fertilisation. This reprogramming process involves global DNA demethylation, changes in nuclear morphology as well as remodeling of repressive histone modifications. Here, using combined cytological and Hi-C based methods, we reveal that following the epigenetic reprogramming and their commitment to gametogenesis, pre-meiotic gonadal germ cells are characterised by a novel principle of chromosome and genome architecture. This involves separation of individual chromosomes and anchoring of centromeres at the nuclear periphery, reduction of  inter-chromosome interactions and disentangling of chromosome ends. Furthermore, genome-wide mapping documents striking remodeling of 3D genome architecture across all observable levels including disruption of topological associated domains (TADs), loss of detectable loops and reduced active-active compartment interactions. We further show that the diminished TADs correlate with the reduced levels of CTCF thus providing a unique in vivo physiological model to understand genome folding principles. Last, but not least we show that primordial germ cell like cells (PGCLCs), derived from embryonic stem cells, do not exhibit the same chromatin organisation as embryonic germ cells suggesting that the 3D genome remodeling accompanies acquisition of meiotic competency. Collectively, our findings uncover the existence of a unique chromatin architecture in premeiotic male and female gonadal germ cells and document that alongside global DNA demethylation the germline epigenetic reprogramming involves erasure of memory at the genome architectural level through a complete re-organisation of 3D genome. Overall design: Hi-C experiments on isolated PGC and somatic cells from female and male E13.5 mouse embryos