Preventing cytoplasmic relocalisation of Tfe3 blocks the loss of

Preventing cytoplasmic relocalisation of Tfe3 blocks the loss of ES cell pluripotency [ 35]. Interestingly, Wnts have recently been demonstrated to sustain ES cells in culture BMN 673 manufacturer when provided alongside LIF [36••]. Although this

has been proposed to occur by blockade of the ES to EpiSC transition, the mechanisms involved are not fully resolved [37]. Gene repression by TCF3 appears to play a part and has been proposed to explain how GSK3β inhibition can promote ES cell self-renewal [38 and 39]. Interestingly, the Nanog target gene Esrrb is amongst the most functionally relevant targets of GSK3β inhibition [40•]. Recently, E-cadherin, which is physically linked to Wnt signalling Selleck Neratinib via β-catenin, has been demonstrated to cooperate with LIFR/gp130 for LIF signalling [41], which could contribute

to the Wnt mediated effect. Relative to the in vitro generation of EpiSC, reprogramming by enforced expression can provide complementary information on the role of TFs in promoting acquisition of pluripotency. Nanog is not in the original reprogramming factor cocktail [ 42]. However, Nanog is expressed late during reprogramming [ 43, 44 and 45•] and is required to complete reprogramming [ 6]. Nanog−/− somatic cells can be reprogrammed to a state in which they acquire the morphology and growth factor dependence of ES cells [ 6]. However, as they neither activate endogenous pluripotency TF gene transcription, nor silence the reprogramming factor transgenes they are not fully reprogrammed [ 6]. This is interesting in light of recent data suggesting that pre-iPS cells may have high Oct4 transgene expression, which is incompatible with self-renewal of ES/iPS cells [ 46• and 47]. Restoring Nanog expression to partially reprogrammed lines facilitates the transition to a fully reprogrammed state [ 6]. This raises Tacrolimus (FK506) the intriguing possibility that Nanog plays a critical role in imposing the transcriptional and epigenetic state required to silence transgene expression. Recent evidence provides

some insight into the mechanisms by which Nanog may achieve reprogramming. Forced expression of the direct Nanog target gene Esrrb, in Nanog−/− pre-iPS cells triggers complete reprogramming when combined with 5’Azacytidine treatment [ 33••]. Furthermore, Nanog interacts with Tet1 ([ 48••] and our unpublished information) and induces Tet2 expression ([ 33•• and 48••] and Figure 2). Concomitant elevation of Tet1 and Nanog in Nanog−/− pre-iPSCs cooperatively enhances iPS cell generation [ 48••]. The overlap in chromatin binding between Tet1 and Nanog suggests that Nanog may bring Tet1 to the methylated regulatory regions of key pluripotency genes, thereby triggering hydroxymethylation, potential subsequent demethylation and activation of the PGRN.

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