Connecting LIF/Stat3 signaling to the naive pluripotency network

LIF signaling, through the transcription factor Stat3, sustains the self-renewal of pluripotent mouse Embryonic Stem (ES) cells. Several targets of Stat3 have previously been identified, most notably the reprogramming factor Klf4. However, such factors are neither required nor sufficient for the potent effect of LIF, suggesting the presence of a yet unidentified Stat3 target.

This prompted Graziano Martello, a member of the Smith lab, to search for the missing factor.  

In collaboration with Paul Bertone, a scientist at the European Bioinformatics Institute, a set of candidate transcription factor effectors has been identified through comparative transcriptome analysis intersected with genome location data for Stat3.

Among these, Tfcp2l1 (also known as Crtr-1) was most abundant. Constitutive expression of Tfcp2l1 effectively substituted for LIF or Stat3 in sustaining self-renewal and pluripotency. Conversely, knockdown of Tfcp2l1 profoundly compromised responsiveness to LIF. Moreover, Tfcp2l1 is both necessary and sufficient to direct molecular reprogramming of post-implantation epiblast stem cells to naïve pluripotency. These results establish Tfcp2l1 as the principal bridge between LIF/Stat3 input and the transcription factor core of naïve pluripotency.

Read the full article at The EMBO Journal

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