Two faces of bivalent domain regulate VEGFA responsiveness and angiogenesis

Jiahuan Chen; Xiaodong Liang; Shasha Zhang; Shiyan Wang; Sara P Garcia; Pengyi Yan; Huijing Yu; Zixuan Li; Li Liu; Fang Zhang; Weiting Wei; Huangying Le; Yan Zhang; Guo-Cheng Yuan; Sun Chen; Yingwei Chen; Kun Sun; William T Pu; Bing Zhang

doi:10.1038/s41419-020-2228-3

Two faces of bivalent domain regulate VEGFA responsiveness and angiogenesis

Cell Death Dis. 2020 Jan 30;11(1):75. doi: 10.1038/s41419-020-2228-3.

Authors

Jiahuan Chen^#¹, Xiaodong Liang^#¹, Shasha Zhang¹, Shiyan Wang^{1

2}, Sara P Garcia³, Pengyi Yan¹, Huijing Yu¹, Zixuan Li¹, Li Liu¹, Fang Zhang¹, Weiting Wei¹, Huangying Le¹, Yan Zhang⁴, Guo-Cheng Yuan³, Sun Chen¹, Yingwei Chen¹, Kun Sun¹, William T Pu^{5

6}, Bing Zhang⁷

Affiliations

¹ Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
² School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian, 223003, China.
³ Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, 02215, USA.
⁴ Renji-Med Clinical Stem Cell Research Center, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China.
⁵ Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA.
⁶ Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
⁷ Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China. bingzhang@sjtu.edu.cn.

^# Contributed equally.

Abstract

The bivalent domain (BD) at promoter region is an unique epigenetic feature poised for activation or repression during cell differentiation in embryonic stem cell. However, the function of BDs in already differentiated cells remains exclusive. By profiling the epigenetic landscape of endothelial cells during VEGFA (vascular endothelial growth factor A) stimulation, we discovered that BDs are widespread in endothelial cells and preferentially marked genes responsive to VEGFA. The BDs responsive to VEGFA have more permissive chromatin environment comparing to other BDs. The initial activation of bivalent genes depends on RNAPII pausing release induced by EZH1 rather than removal of H3K27me3. The later suppression of bivalent gene expression depended on KDM5A recruitment by its interaction with PRC2. Importantly, EZH1 promoted both in vitro and in vivo angiogenesis by upregulating EGR3, whereas KDM5A dampened angiogenesis. Collectively, this study demonstrates a novel dual function of BDs in endothelial cells to control VEGF responsiveness and angiogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Movement / drug effects
Cell Movement / genetics
Chromatin / metabolism
Chromatin Immunoprecipitation Sequencing
Early Growth Response Protein 3 / metabolism
Embryonic Stem Cells / drug effects
Embryonic Stem Cells / metabolism
Endothelial Cells / drug effects
Endothelial Cells / metabolism*
Epigenesis, Genetic
Histones / metabolism*
Human Umbilical Vein Endothelial Cells
Humans
Mice
Neovascularization, Physiologic / genetics*
Polycomb Repressive Complex 2 / metabolism
Promoter Regions, Genetic / genetics*
Protein Domains / genetics
RNA Polymerase II / metabolism
RNA, Small Interfering
RNA-Seq
Retinoblastoma-Binding Protein 2 / metabolism
Up-Regulation
Vascular Endothelial Growth Factor A / pharmacology*

Substances

Chromatin
EGR3 protein, human
Histones
RNA, Small Interfering
VEGFA protein, human
Vascular Endothelial Growth Factor A
Early Growth Response Protein 3
KDM5A protein, human
Retinoblastoma-Binding Protein 2
EZH1 protein, human
Polycomb Repressive Complex 2
RNA Polymerase II