The establishment of cell fates involves alterations of transcription factor 
repertoires and repurposing of transcription factors by post-translational 
modifications. In embryonic stem cells (ESCs), the chromatin organizers SATB2 
and SATB1 balance pluripotency and differentiation by activating and repressing 
pluripotency genes, respectively. Here, we show that conditional Satb2 gene 
inactivation weakens ESC pluripotency, and we identify SUMO2 modification of 
SATB2 by the E3 ligase ZFP451 as a potential driver of ESC differentiation. 
Mutations of two SUMO-acceptor lysines of Satb2 (Satb2K →R ) or knockout of 
Zfp451 impair the ability of ESCs to silence pluripotency genes and activate 
differentiation-associated genes in response to retinoic acid (RA) treatment. 
Notably, the forced expression of a SUMO2-SATB2 fusion protein in either Satb2K 
→R or Zfp451-/- ESCs rescues, in part, their impaired differentiation potential 
and enhances the down-regulation of Nanog The differentiation defect of Satb2K 
→R ESCs correlates with altered higher-order chromatin interactions relative to 
Satb2wt ESCs. Upon RA treatment of Satb2wt ESCs, SATB2 interacts with ZFP451 and 
the LSD1/CoREST complex and gains binding at differentiation genes, which is not 
observed in RA-treated Satb2K →R cells. Thus, SATB2 SUMOylation may contribute 
to the rewiring of transcriptional networks and the chromatin interactome of 
ESCs in the transition of pluripotency to differentiation.