In pluripotent stem cells, bivalent domains mark the promoters of developmentally regulated loci. Histones in these chromatin regions contain coincident epigenetic modifications of gene activation and repression. How these marks are transmitted to maintain the pluripotent state in daughter progeny remains poorly understood. Our study demonstrates that Oct4 post-translational modifications (PTMs) form a positive feedback loop, which promotes Akt activation and interaction with Hmgb2 and the SET complex. This preserves H3K27me3 modifications in daughter progeny and maintains the pluripotent gene expression signature in murine embryonic stem cells. However, if Oct4 is not phosphorylated, a negative feedback loop is formed that inactivates Akt and initiates the DNA damage response. Oct4 sumoylation then is required for G1/S progression and transmission of the repressive H3K27me3 mark. Therefore, PTMs regulate the ability of Oct4 to direct the spatio-temporal formation of activating and repressing complexes to orchestrate chromatin plasticity and pluripotency. Our work highlights a previously unappreciated role for Oct4 PTM-dependent interactions in maintaining restrained Akt signaling and promoting a primitive epigenetic state.
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