Dynamic and integrated transcriptional code orchestrates the angiogenic response [Seq]

Epigenetic modifications and transcription factors form a chromatin code to regulate gene expression in many physiological and pathological processes. However, little is known about whether the environmental stimuli could interplay with this code and regulate the transcription and biological functions. Here, we interrogated the chromatin state of multiple epigenetic modifications and transcription factors during a time course of VEGF stimulation in the endothelial cells and found a broad change of transcriptome induced by VEGF. At the promoter-proximal regions, a unique epigenetic pattern of bivalent domain preferentially governed the part of transcriptome change by hijacking the EZH1 transcriptional activity. VEGF substantially altered the epigenetic landscape at enhancer regions and transcription factor chromatin occupancy across the genome, which significantly accounted for the change of VEGF-downstream gene expression. Moreover, by integrating a transcription-regulatory network of VEGF pathway, we discovered MAFs as a novel mater transcriptional factor controlling the VEGF transcriptional program and angiogenesis. Collectively, these results revealed the extracellular stimulus of VEGF in fact implements a significant reconfiguration of chromatin code that coordinately regulates the angiogenic response. RNA-seq on HUVEC after VEGF stimulation at 0,1,4,12 hours. ChIP-seq of H3K27ac, H3K27me3, H3K4me1, 2, 3, H3K36me3, RNAPII, ETS1, ERG1, FLI, JUN, RBPJ, GATA2, p300 and EZH2 on HUVEC after VEGF stimulation at 0, 1, 4, 12 hour.