A Repressive Type of TEAD4 Condensation and Engineering a Glue Peptide Therapy Against Cancer [Cut&Tag]

Transcriptional factors (TFs) act as central determinants to coordinate cell death and survival by differentially modulating gene expression. Here, we systematically identified many TFs including TEAD4 forming condensates in stressed cells. In sharp contrast to YAP-induced transcription-activating condensation of TEAD4, we found co-factors such as VGLL4 and RFXANK could alternatively induce repressive condensation of TEAD4 to trigger cell death. Illustrated by VGLL4, we mechanistically revealed that the heterotypic interactions between TEAD4 with VGLL4 favors its oligomerization and assembly of large condensates 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 (GLUP) to selectively “glue” TEAD4 molecules together, therefore forcefully driving its repressive condensation against 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, and revealed how cofactor-induced differential condensation orchestrate opposite functions of a given TF, and further developed a new class of antitumor strategy by artificially inducing repressive condensation.