Identification of a Repressive Type of TF Condensation and Engineering a Glue Peptide Therapy Against Cancer

Transcriptional factors (TFs) act as key determinants of the coordination of cell death and survival by differentially modulating gene expression. Here, we systematically identified many TFs including condensate-forming TEAD4 in stressed cells. In sharp contrast to YAP-induced transcription-activating condensation of TEAD4, we found that co-factors such as VGLL4 and RFXANK could alternatively induce repressive condensation of TEAD4 to trigger cell death. Illustrated using VGLL4 as the cofactor, we mechanistically revealed that the heterotypic interactions between TEAD4 and VGLL4 favor the oligomerization and assembly of large condensates of TEAD4 to manifest a nonclassical inhibitory function of this transcription factor, i.e., causing DNA/chromatin to be aggregated and entangled, which eventually impede gene expression. Based on these findings, we engineered a linker peptide to selectively “glue” TEAD4 molecules together, thereby forcefully driving its condensation-induced repression of YAP-induced activation. This glue peptide displayed a strong antitumor effect via inhibition of TEAD4-related gene transcription. Collectively, this work revealed a new type of phase separation, i.e., repressive condensation of TFs, revealed how cofactor-induced differential condensation can orchestrate opposite functions of a given TF, and further developed a new class of antitumor strategies involving artificially inducing repressive condensation.