Abstract
Yes-associated protein 1 (YAP) is a transcriptional regulator with critical roles in mechanotransduction, organ size control, and regeneration. Here, using advanced tools for real-time visualization of native YAP and target gene transcription dynamics, we show that a cycle of fast exodus of nuclear YAP to the cytoplasm followed by fast reentry to the nucleus (“localization-resets”) activates YAP target genes. These “resets” are induced by calcium signaling, modulation of actomyosin contractility, or mitosis. Using nascent-transcription reporter knock-ins of YAP target genes, we show a strict association between these resets and downstream transcription. Oncogenically-transformed cell lines lack localization-resets and instead show dramatically elevated rates of nucleocytoplasmic shuttling of YAP, suggesting an escape from compartmentalization-based control. The single-cell localization and transcription traces suggest that YAP activity is not a simple linear function of nuclear enrichment and point to a model of transcriptional activation based on nucleocytoplasmic exchange properties of YAP.
Highlights
Yes-associated protein 1 (YAP) is a transcriptional regulator with critical roles in mechanotransduction, organ size control, and regeneration
We found the nucleocytoplasmic ratio (N/C) of eGFP and native-YAP staining (Fig. 1c, d) were highly correlated on a per-cell basis, indicating proper integration of the eGFP tag
To test if a fundamental connection exists between YAP shuttling and the transcription of YAP-responsive genes in the context of native cellular processes, we investigated mitosis, since mitotic chromatin condensation has been deemed as a major mediator of transcription factors (TFs) displacement from bulk chromatin[59]
Summary
Yes-associated protein 1 (YAP) is a transcriptional regulator with critical roles in mechanotransduction, organ size control, and regeneration. Using advanced tools for real-time visualization of native YAP and target gene transcription dynamics, we show that a cycle of fast exodus of nuclear YAP to the cytoplasm followed by fast reentry to the nucleus (“localization-resets”) activates YAP target genes. These “resets” are induced by calcium signaling, modulation of actomyosin contractility, or mitosis. Patient derived triple negative breast cancer lines harboring either HRas or KRas mutations show this defect Together, these results suggest a model of transcriptional activation gated by tight control of YAP localization, where Ras transformation bypasses this control allowing permanent activation of the YAP transcriptional program
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