A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis

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. Synopsis Liquid–liquid phase separation of transcription factors has been shown to activate transcription. This study identifies a repressive type of transcription factor condensation induced by TEAD4 co-factor binding, leading to DNA/chromatin aggregation. Binding of transcriptional co-factors VGLL4 and RFXANK induces formation of large condensates of TEAD4 in cells under glucose starvation. VGLL4-induced condensation of TEAD4 represses its YAP-dependent transcriptional activation. Repressive condensation of TEAD4 causes chromatin aggregation and cell death. A “glue peptide” derived from the TEAD4-binding motif of VGLL4 induces TEAD4 condensation and suppresses tumorigenesis in mice. Glucose deprivation-dependent co-factor binding induces TEAD4 condensation, suppressing its transcriptional activity and inhibiting gastric tumorigenesis in mice.