Phase separation of TAZ compartmentalizes the transcription machinery to promote gene expression

Abstract

TAZ promotes cell proliferation, development, and tumorigenesis by regulating target gene transcription. However, how TAZ orchestrates the transcriptional responses remains poorly defined. Here we demonstrate that TAZ forms nuclear condensates via liquid-liquid phase separation to compartmentalize its DNA binding co-factor TEAD4, the transcription co-activators BRD4 and MED1 and the transcription elongation factor CDK9 for activation of gene expression.TAZ, but not its paralog YAP, forms phase-separated droplets in vitro and liquid-like nuclear condensates in vivo, and this ability is negatively regulated by Hippo signaling via LATS-mediated phosphorylation and mediated by the coiled-coil domain. Deletion of the TAZ coiled-coil domain or substitution with the YAP coiled-coil domain does not affect the interaction of TAZ with its partners, but prevents its phase separation and more importantly, its ability to induce target gene expression. Thus, our study identifies a novel mechanism for the transcriptional activation by TAZ and demonstrates for the first time that pathway-specific transcription factors also engage the phase separation mechanism for efficient transcription activation.

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

“…The coiled-coil domain of TAZ, but not of YAP, is able to induce phase separation by forming liquid-like biomolecular condensates that compartmentalize and concentrate its DNA-binding cofactor TEAD4, coactivators BRD4 and MED1 and the transcription elongation factor CDK9 on TAZ-specific target genes. This ability was blocked by LATS-mediated TAZ serine phosphorylation [111].…”

Protein phase separation and its role in tumorigenesis

“…Recent evidence shows that YAP and TAZ assemble into condensates in vitro and in vivo ( Cai et al, 2019 ; Lu et al, 2020 ; Table 1 and Figure 4 ). In cells, YAP assembles into condensates at super-enhancer regions and these nuclear condensates contain TAZ but also the transcription factor TEAD1.…”

“…These condensates appear to recruit RNA polymerase II to trigger the transcription of proliferative genes ( Cai et al, 2019 ). Furthermore, YAP and TAZ mutants defective in condensate formation, displayed reduced transcriptional activity, suggesting that transcriptional activity of YAP and TAZ is associated with their ability to assemble into condensates ( Cai et al, 2019 ; Lu et al, 2020 ). Importantly, TAZ-containing condensates are negatively regulated by Hippo signaling and sensitive to mechanical signals ( Lu et al, 2020 ).…”

Protein phase separation: A novel therapy for cancer?

“…Subsequently, there is growing evidence that phase separation plays an important role in transcriptional regulation. YAP and TAZ, pervasively activated transcription factors in cancers, promote specific gene expression through phase separation (Cai et al, 2019;Franklin & Guan, 2020;Lu et al, 2020). Moreover, heat shock transcription factor 1 (HSF1), which is closely associated with malignant evolution of cancers, forms phase-separated nuclear stress bodies that can sequester HSF1 and thus down-regulate its function (Gaglia et al, 2020).…”