Erase–Maintain–Establish: Natural Reprogramming of the Mammalian Epigenome

The genetic information is largely identical across most cell types in a given organism but the epigenome, which controls expression of the genome, is cell type- and context-dependent. Although most mature mammalian cells appear to have a stable, heritable epigenome, a dynamic intricate process reshapes it as these cells transition from soma to germline and back again. During normal embryogenesis, primordial germ cells, of somatic origin, are set aside to become gametes. In doing so their genome is reprogrammed-that is, the epigenome of specific regions is replaced in a sex-specific fashion as they terminally differentiate into oocytes or spermatocytes in the gonads. Upon union of these gametes, reprogramming of the new organism's epigenome is initiated, which eventually leads, through pluripotent cells, to the cell lineages required for proper embryonic development to a sexually mature adult. This never-ending cycle of birth and rebirth is accomplished through methylation and demethylation of specific genomic sites within the gametes and pluripotent cells of an organism. This enigmatic process of natural epigenomic reprogramming is now being dissected in vivo, focusing on specific genomic regions-that is, imprinted genes and retrotransposons, where TRIM28 molecular complexes appear to guide the transition from gamete to embryo.