YAP charge patterning mediates signal integration through transcriptional co-condensates

Abstract

Abstract Transcription factor dynamics are used to selectively engage gene regulatory programs. Biomolecular condensates have emerged as an attractive signaling module in this process, but the underlying mechanisms are not well-understood. Here, we probe the molecular basis of YAP signal integration through transcriptional condensates. Leveraging light-sheet single-molecule imaging and synthetic condensates, we demonstrate charge-mediated co-condensation of the transcriptional regulators YAP and Mediator into transcriptionally active condensates in stem cells. Intrinsically disordered region sequence analysis and YAP protein engineering demonstrate that the signaling specificity of YAP is established, in part, through complementary electrostatic interactions between negatively charged blocks within YAP and positively charged blocks within Mediator. YAP/Mediator co-condensation is counteracted by negative feedback from transcription, driving an adaptive transcriptional response that is well-suited for decoding dynamic inputs. Our work reveals a molecular framework for YAP condensate formation and sheds light on the function of YAP condensates for emergent gene regulatory behavior.