Phase separation of YAP reorganizes genome topology for long-term YAP target gene expression

Nat Cell Biol. 2019 Dec;21(12):1578-1589. doi: 10.1038/s41556-019-0433-z. Epub 2019 Dec 2.

Abstract

Yes-associated protein (YAP) is a transcriptional co-activator that regulates cell proliferation and survival by binding to a select set of enhancers for target gene activation. How YAP coordinates these transcriptional responses is unknown. Here, we demonstrate that YAP forms liquid-like condensates in the nucleus. Formed within seconds of hyperosmotic stress, YAP condensates compartmentalized the YAP transcription factor TEAD1 and other YAP-related co-activators, including TAZ, and subsequently induced the transcription of YAP-specific proliferation genes. Super-resolution imaging using assay for transposase-accessible chromatin with photoactivated localization microscopy revealed that the YAP nuclear condensates were areas enriched in accessible chromatin domains organized as super-enhancers. Initially devoid of RNA polymerase II, the accessible chromatin domains later acquired RNA polymerase II, transcribing RNA. The removal of the intrinsically-disordered YAP transcription activation domain prevented the formation of YAP condensates and diminished downstream YAP signalling. Thus, dynamic changes in genome organization and gene activation during YAP reprogramming is mediated by liquid-liquid phase separation.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Line
  • Cell Nucleus / genetics
  • Chromatin / genetics
  • Female
  • Gene Expression Regulation / genetics*
  • Genome / genetics*
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Mice
  • Nuclear Proteins / genetics
  • RNA Polymerase II / genetics
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription, Genetic / genetics
  • Transcriptional Activation / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Chromatin
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Yap1 protein, mouse
  • RNA Polymerase II