TY - JOUR
T1 - Phase separation of YAP reorganizes genome topology for long-term YAP target gene expression
AU - Cai, Danfeng
AU - Feliciano, Daniel
AU - Dong, Peng
AU - Flores, Eduardo
AU - Gruebele, Martin
AU - Porat-Shliom, Natalie
AU - Sukenik, Shahar
AU - Liu, Zhe
AU - Lippincott-Schwartz, Jennifer
N1 - Funding Information:
1Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. 2Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA. 3Thoracic and Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 4Department of Chemistry and Chemical Biology, University of California, Merced, CA, USA. 5Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL, USA. *e-mail: lippincottschwartzj@janelia.hhmi.org
Funding Information:
We thank the members of the J.L.-S. lab for their helpful discussions and critical comments. Support for this work was received from the Howard Hughes Medical Institute (to J.L.-S. and Z.L.), Damon Runyon Cancer Research Foundation (grant no. DRG-2233-15 to D.C.), and intramural research funding from the NIH. We also appreciate the help we received from the Flow Cytometry Core Facility of the NEI/NIH.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41556-019-0433-z
DO - 10.1038/s41556-019-0433-z
M3 - Article
C2 - 31792379
AN - SCOPUS:85076167212
VL - 21
SP - 1578
EP - 1589
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 12
ER -