YAP charge patterning mediates signal integration through transcriptional co-condensates

Abstract

Transcription factor dynamics are used to selectively engage gene regulatory programs. Biomolecular condensates have emerged as an attractive signaling substrate in this process, but the underlying mechanisms are not well-understood. Here, we probed 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. IDR sequence analysis and YAP protein engineering demonstrate that instead of the net charge, YAP signaling specificity is established through its negative charge patterning that interacts with Mediator’s positive charge blocks. The mutual enhancement of 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 new light on the function of YAP condensates for emergent gene regulatory behavior.