VEGF amplifies transcription through ETS1 acetylation to enable angiogenesis

Jiahuan Chen, Yi Fu, Daniel S. Day, Ye Sun, Shiyan Wang, Xiaodong Liang, Fei Gu, Fang Zhang, Sean M. Stevens, Pingzhu Zhou, Kai Li, Yan Zhang, Ruei-zeng Lin, Lois E. H. Smith, Jin Zhang, Kun Sun, Juan M. Melero-Martin, Zeguang Han, Peter J. Park, Bing Zhang () and William T. Pu ()
Additional contact information
Jiahuan Chen: Shanghai Jiao Tong University
Yi Fu: Shanghai Jiao Tong University
Daniel S. Day: Harvard Medical School
Ye Sun: Harvard Medical School/Children’s Hospital Boston
Shiyan Wang: Shanghai Jiao Tong University
Xiaodong Liang: Shanghai Jiao Tong University
Fei Gu: Boston Children’s Hospital
Fang Zhang: Shanghai Jiao Tong University
Sean M. Stevens: Boston Children’s Hospital
Pingzhu Zhou: Boston Children’s Hospital
Kai Li: Boston Children’s Hospital
Yan Zhang: Shanghai Jiao Tong University
Ruei-zeng Lin: Children’s Hospital Boston
Lois E. H. Smith: Harvard Medical School/Children’s Hospital Boston
Jin Zhang: Boston Children’s Hospital
Kun Sun: Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Juan M. Melero-Martin: Children’s Hospital Boston
Zeguang Han: Shanghai Jiao Tong University
Peter J. Park: Harvard Medical School
Bing Zhang: Shanghai Jiao Tong University
William T. Pu: Boston Children’s Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Release of promoter-proximally paused RNA polymerase II (RNAPII) is a recently recognized transcriptional regulatory checkpoint. The biological roles of RNAPII pause release and the mechanisms by which extracellular signals control it are incompletely understood. Here we show that VEGF stimulates RNAPII pause release by stimulating acetylation of ETS1, a master endothelial cell transcriptional regulator. In endothelial cells, ETS1 binds transcribed gene promoters and stimulates their expression by broadly increasing RNAPII pause release. 34 VEGF enhances ETS1 chromatin occupancy and increases ETS1 acetylation, enhancing its binding to BRD4, which recruits the pause release machinery and increases RNAPII pause release. Endothelial cell angiogenic responses in vitro and in vivo require ETS1-mediated transduction of VEGF signaling to release paused RNAPII. Our results define an angiogenic pathway in which VEGF enhances ETS1–BRD4 interaction to broadly promote RNAPII pause release and drive angiogenesis.

Date: 2017
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DOI: 10.1038/s41467-017-00405-x

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