Transcriptional factors (TFs) act as key determinants of cell death and survival by differentially modulating gene expression. Here, we identified many TFs, including TEAD4, that form condensates in stressed cells. In contrast to YAP-induced transcription-activating condensates of TEAD4, we found that co-factors such as VGLL4 and RFXANK alternatively induced repressive TEAD4 condensates to trigger cell death upon glucose starvation. Focusing on VGLL4, we demonstrated that heterotypic interactions between TEAD4 and VGLL4 favor the oligomerization and assembly of large TEAD4 condensates with a nonclassical inhibitory function, i.e., causing DNA/chromatin to be aggregated and entangled, which eventually impede gene expression. Based on these findings, we engineered a peptide derived from the TEAD4-binding motif of VGLL4 to selectively induce TEAD4 repressive condensation. This "glue" peptide displayed a strong antitumor effect in genetic and xenograft mouse models of gastric cancer via inhibition of TEAD4-related gene transcription. This new type of repressive TF phase separation exemplifies how cofactors can orchestrate opposite functions of a given TF, and offers potential new antitumor strategies via artificial induction of repressive condensation.

中文翻译：

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合成肽可诱导辅因子诱导的抑制性转录因子凝聚，以抑制肿瘤发生。


转录因子 （TFs） 通过差异调节基因表达，成为细胞死亡和存活的关键决定因素。在这里，我们鉴定了许多在应激细胞中形成凝聚物的 TFs，包括 TEAD4。与 YAP 诱导的 TEAD4 转录激活浓缩物相比，我们发现 VGLL4 和 RFXANK 等辅助因子交替诱导抑制性 TEAD4 浓缩物在葡萄糖饥饿时触发细胞死亡。专注于 VGLL4，我们证明了 TEAD4 和 VGLL4 之间的异型相互作用有利于具有非经典抑制功能的大 TEAD4 缩合物的寡聚化和组装，即导致 DNA/染色质聚集和缠结，最终阻碍基因表达。基于这些发现，我们设计了一种源自 VGLL4 的 TEAD4 结合基序的肽，以选择性诱导 TEAD4 抑制性缩合。这种“胶”肽通过抑制 TEAD4 相关基因转录，在胃癌的遗传和异种移植小鼠模型中显示出很强的抗肿瘤作用。这种新型的抑制性 TF 相分离说明了辅因子如何协调给定 TF 的相反功能，并通过人工诱导抑制性凝聚提供了潜在的新抗肿瘤策略。