Department of Cancer Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
J Biol Chem. 2013 Aug 16;288(33):24234-46. doi: 10.1074/jbc.M113.469783. Epub 2013 Jun 12.
Pluripotent embryonic stem cells (ESCs) undergo self-renewal until stimulated to differentiate along specific lineage pathways. Many of the transcriptional networks that drive reprogramming of a self-renewing ESC to a differentiating cell have been identified. However, fundamental questions remain unanswered about the epigenetic programs that control these changes in gene expression. Here we report that the histone ubiquitin hydrolase ubiquitin-specific protease 22 (USP22) is a critical epigenetic modifier that controls this transition from self-renewal to differentiation. USP22 is induced as ESCs differentiate and is necessary for differentiation into all three germ layers. We further report that USP22 is a transcriptional repressor of the locus encoding the core pluripotency factor sex-determining region Y-box 2 (SOX2) in ESCs, and this repression is required for efficient differentiation. USP22 occupies the Sox2 promoter and hydrolyzes monoubiquitin from ubiquitylated histone H2B and blocks transcription of the Sox2 locus. Our study reveals an epigenetic mechanism that represses the core pluripotency transcriptional network in ESCs, allowing ESCs to transition from a state of self-renewal into lineage-specific differentiation programs.
多能胚胎干细胞（ESCs）在受到刺激沿着特定谱系途径分化之前会进行自我更新。已经确定了许多驱动将自我更新的 ESC 重编程为分化细胞的转录网络。然而，关于控制这些基因表达变化的表观遗传程序，仍有一些基本问题尚未得到解答。在这里，我们报告组蛋白泛素水解酶泛素特异性蛋白酶 22（USP22）是一种关键的表观遗传修饰因子，可控制从自我更新到分化的这种转变。USP22 在 ESC 分化时被诱导，并且是分化为所有三个胚层所必需的。我们进一步报告，USP22 是 ESC 中编码核心多能因子性别决定区 Y 框 2（SOX2）的基因座的转录抑制剂，并且这种抑制对于有效的分化是必需的。USP22 占据 Sox2 启动子并从泛素化组蛋白 H2B 上水解单泛素，从而阻止 Sox2 基因座的转录。我们的研究揭示了一种表观遗传机制，该机制抑制了 ESC 中的核心多能转录网络，使 ESC 能够从自我更新状态过渡到谱系特异性分化程序。
