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 (Satb2^{K →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 Satb2^{K →R} or Zfp451^−/− ESCs rescues, in part, their impaired differentiation potential and enhances the down-regulation of Nanog. The differentiation defect of Satb2^{K →R} ESCs correlates with altered higher-order chromatin interactions relative to Satb2^wt ESCs. Upon RA treatment of Satb2^wt ESCs, SATB2 interacts with ZFP451 and the LSD1/CoREST complex and gains binding at differentiation genes, which is not observed in RA-treated Satb2^{K →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.

中文翻译：

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ZFP451 介导的 SATB2 SUMOylation 驱动胚胎干细胞分化

细胞命运的建立涉及转录因子库的改变和通过翻译后修饰对转录因子的再利用。在胚胎干细胞 (ESC) 中，染色质组织者 SATB2 和 SATB1 分别通过激活和抑制多能性基因来平衡多能性和分化。在这里，我们表明条件性 Satb2基因失活削弱了 ESC 多能性，我们确定 E3 连接酶 ZFP451 对 SATB2 的 SUMO2 修饰是 ESC 分化的潜在驱动因素。Satb2 ( Satb2 ^{K → R} )的两个相扑受体赖氨酸的突变或Zfp451的敲除损害 ESC 沉默多能性基因和激活分化相关基因以响应视黄酸 (RA) 治疗的能力。值得注意的是，SUMO2-SATB2 融合蛋白在Satb2 ^{K → R}或Zfp451 ^{-/- ESC 中的强制表达部分挽救了它们受损的分化潜能并增强了}Nanog的下调。Satb2 ^{K → R} ESCs的分化缺陷与相对于Satb2 ^wt ESCs改变的高阶染色质相互作用相关。Satb2 ^wt的 RA 治疗后ESC、SATB2 与 ZFP451 和 LSD1/CoREST 复合物相互作用并在分化基因处获得结合，这在 RA 处理的Satb2 ^{K → R}细胞中未观察到。因此，SATB2 SUMOylation 可能有助于转录网络的重新布线和 ESC 在多能性向分化转变中的染色质相互作用组。