Two faces of bivalent domain regulate VEGFA responsiveness and angiogenesis

The bivalent domain at promoter region is a unique epigenetic feature poised for activation or repression during cell differentiation in embryonic stem cell. However, the function of bivalent domains in already differentiated cells remains exclusive. By profiling the epigenetic landscape of endothelial cells during VEGFA stimulation, we discovered that bivalent domains are widespread in endothelial cells and preferentially marked genes responsive to VEGFA. The bivalent domains responsive to VEGFA have more permissive chromatin environment comparing to other bivalent domains. 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 demonstrated a novel dual function of bivalent domains in endothelial cells to control VEGF responsiveness and angiogenesis. Overall design: Our model system consisted of human umbilical vein endothelial cells that were cultured overnight in low serum and no VEGFA, and then stimulated for 12 hours with 50 ng/ml VEGFA. Samples were collected at 0 (unstimulated), 1, 4, and 12 hours. ChIP-seq of corresponding factors or histone markers were sequenced.