Tgif1 Counterbalances the Activity of Core Pluripotency Factors in Mouse Embryonic Stem Cells

• The level of Tgif1 is regulated by embryonic stem cell (ESC) core pluripotency factors
• Tgif1 is an integral component of the ESC core regulatory network
• Tgif1 counterbalances the levels of the core pluripotency factors
• Tgif1 functions independently of the TGFβ/activin/nodal signaling in mouse ESCs

SummaryCore pluripotency factors, such as Oct4, Sox2, and Nanog, play important roles in maintaining embryonic stem cell (ESC) identity by autoregulatory feedforward loops. Nevertheless, the mechanism that provides precise control of the levels of the ESC core factors without indefinite amplification has remained elusive. Here, we report the direct repression of core pluripotency factors by Tgif1, a previously known terminal repressor of TGFβ/activin/nodal signaling. Overexpression of Tgif1 reduces the levels of ESC core factors, whereas its depletion leads to the induction of the pluripotency factors. We confirm the existence of physical associations between Tgif1 and Oct4, Nanog, and HDAC1/2 and further show the level of Tgif1 is not significantly altered by treatment with an activator/inhibitor of the TGFβ/activin/nodal signaling. Collectively, our findings establish Tgif1 as an integral member of the core regulatory circuitry of mouse ESCs that counterbalances the levels of the core pluripotency factors in a TGFβ/activin/nodal-independent manner.

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