Figure 3.

Schematic representation comparing the role of Nanog during development and reprogramming. Nanog interacts with other pluripotency TFs, as well as chromatin remodellers, such as NuRD and Tet1. By recruiting proteins to target gene chromatin Nanog can induce or repress mediators of self-renewal and differentiation. (a) Nanog is required twice during development: for the correct specification of a pluripotent epiblast in the blastocyst and for completion of germ cell development beyond E11.5. In both contexts Nanog may operate by modulating expression of its target genes and by counteracting accumulation of 5-methyl-cytosine at regulatory elements and consequent epigenetic silencing of key pluripotency genes. Nanog downregulation appears to be required in the epiblast to reduce expression of pluripotency TFs and allow dismantling of the pre-implantation PGRN. (b) Overexpression of Nanog induces LIF independent self-renewal and blocks ES cell differentiation. Nanog^−/− EpiSC can be converted to a pre-implantation pluripotent state by complementation with Nanog or Esrrb. Conversion of wild-type EpiSC to ES cells can be achieved by overexpressing Nanog (possibly through transcriptional activation of the indicated TFs) or Esrrb. An alternative LIF-mediated conversion (which may operate through Klf4 induction) can be accelerated by additional enforced expression of the individual TFs indicated (oval). (c) Nanog expression is required for complete reprogramming of pre-iPSCs from somatic cells, potentially by inducing Esrrb expression and contributing to the reversion of 5-methyl-cytosine marks by Tet1 recruitment. Esrrb can substitute for Nanog during reprogramming of pre-iPSCs when used together with 5-azacytidine. N, Nanog; E, Esrrb; T, Tet1. Boxes associated with arrows indicate potential mechanisms of action.