Meyer Kirstin, Yserentant Klaus, Cheloor-Kovilakam Rasmi, Ruff Kiersten M, Chung Chan-I, Shu Xiaokun, Huang Bo, Weiner Orion D
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
bioRxiv. 2024 Aug 10:2024.08.10.607443. doi: 10.1101/2024.08.10.607443.
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.
转录因子动力学被用于选择性地启动基因调控程序。生物分子凝聚物已成为这一过程中一种引人注目的信号转导底物，但其潜在机制尚未得到充分理解。在这里，我们通过转录凝聚物探究了YAP信号整合的分子基础。利用光片单分子成像和合成凝聚物，我们证明了转录调节因子YAP和中介体通过电荷介导的共凝聚形成干细胞中的转录活性凝聚物。IDR序列分析和YAP蛋白工程表明，YAP信号特异性不是通过净电荷建立的，而是通过其与中介体正电荷块相互作用的负电荷模式建立的。YAP/中介体共凝聚的相互增强被转录的负反馈所抵消，从而驱动一种适合解码动态输入的适应性转录反应。我们的工作揭示了YAP凝聚物形成的分子框架，并为YAP凝聚物在新兴基因调控行为中的功能提供了新的见解。
