Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington's canal

The life cycle of an organism is characterized by phases of reprogramming and differentiation during development from the zygote to the adult organism.Epigenetic reprogramming occurs in primordial germ cells (PGCs) and in the early embryo. Reprogramming is an essential characteristic of the immortality of the germ line in which epigenetic imprints are erased and reset in a parent-of-origin-dependent manner. Epigenetic reprogramming in PGCs and on fertilization is required to restore totipotency in the early embryo and perhaps to erase epimutations.Cells of the early mammalian embryo as well as pluripotent embryonic stem (ES) cells and PGCs are epigenetically dynamic and heterogeneous. During early development, this heterogeneity of epigenetic states is associated with stochastic expression of lineage-determining transcription factors that establish an intimate crosstalk with epigenetic modifiers.Subsequent development is characterized by the progressive restriction of cellular plasticity that is accompanied by the gradual acquisition of epigenetic marks. This epigenetic programming is important for cell differentiation and the specification of the principal cell lineages of the early conceptus.Once the lineages have been specified, DNA methylation of a few crucial loci, notably Elf5 and possibly also Stella (also known as Dppa3), is required to restrict their differentiation potential and to establish lineage-committed cell populations, the fate allocation of which is stably inherited by all descendants.Reversion of developmental progression to generate induced pluripotent stem (iPS) cells that are functionally similar to ES cells can be achieved experimentally by temporal overexpression of a few pluripotency factors, namely OCT4 (encoded by Pou5f1), SRY box-containing factor 2 (SOX2), kruppel-like factor 4 (KLF4) and MYC. iPS cell derivation requires marked epigenetic reprogramming of the parent cell, and its efficiency can be enhanced by inhibitors of epigenetic modifiers.