Resetting the epigenome beyond pluripotency in the germline

Germ cells undergo comprehensive epigenetic reprogramming toward acquiring fitness for pluripotency and totipotency. Notably, the full extent of the epigenetic reprogramming experienced by germ cells remains unmatched by attempts to experimentally restore pluripotency in somatic cells. We propose that the defects present in experimentally generated cells are corrected upon differentiation into the germ cell lineage, as has been observed in cases of germline transmission. Unraveling the mechanisms responsible for germ cell-specific epigenetic reprogramming will likely have important implications for both basic and clinical stem cell research.