SOX2 等先锋转录因子 (TF) 通过增强由共激活子、RNA 和超级增强子 (SE) 上的介体形成的转录凝聚物内的基因表达，对干性和癌症至关重要。尽管它们很重要，但这些因素如何共同作用以实现转录缩合和激活仍不清楚。 SOX2 是在多能细胞和癌症干细胞 SE 中发现的先驱转录因子，通过与核小体结合启动 SE 介导的转录，但其机制尚不完全清楚。为了解决 SOX2 在 SE 中的作用，我们通过生物信息学分析将 mSE078 确定为富含 SOX2 的 SE 模型，将 p300 确定为共激活剂。体外和细胞测定显示 SOX2 与 mSE078 中的 p300 和 SOX2 结合基序形成缩合物。我们进一步证明SOX2缩合与mSE078在细胞中的增强子活性高度相关。此外，我们成功证明 p300 不仅可以提高转录活性，还可以通过与这些转录凝聚物中的 SOX2 直接相互作用来触发染色质乙酰化。最后，我们对富含 SOX2 的 SE 的验证展示了它们对干细胞和癌细胞中靶基因表达的贡献。总的来说，这项研究为 SOX2 及其共激活子 p300 的协同相互作用提供了有价值的机制见解，揭示了富含 SOX2 的 SE 中转录缩合和激活的调节。© 作者 2023。由牛津大学出版社出版代表核酸研究。

Pioneer transcription factors (TFs) like SOX2 are vital for stemness and cancer through enhancing gene expression within transcriptional condensates formed with coactivators, RNAs and mediators on super-enhancers (SEs). Despite their importance, how these factors work together for transcriptional condensation and activation remains unclear. SOX2, a pioneer TF found in SEs of pluripotent and cancer stem cells, initiates SE-mediated transcription by binding to nucleosomes, though the mechanism isn't fully understood. To address SOX2's role in SEs, we identified mSE078 as a model SOX2-enriched SE and p300 as a coactivator through bioinformatic analysis. In vitro and cell assays showed SOX2 forms condensates with p300 and SOX2-binding motifs in mSE078. We further proved that SOX2 condensation is highly correlated with mSE078's enhancer activity in cells. Moreover, we successfully demonstrated that p300 not only elevated transcriptional activity but also triggered chromatin acetylation via its direct interaction with SOX2 within these transcriptional condensates. Finally, our validation of SOX2-enriched SEs showcased their contribution to target gene expression in both stem cells and cancer cells. In its entirety, this study imparts valuable mechanistic insights into the collaborative interplay of SOX2 and its coactivator p300, shedding light on the regulation of transcriptional condensation and activation within SOX2-enriched SEs.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.