Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis.

Endothelial cells (ECs) are phenotypically heterogeneous, mainly due to their dynamic response to the tissue microenvironment. Vascular endothelial cell growth factor (VEGF), the best-known angiogenic factor, activates calcium-nuclear factor of activated T cells (NFAT) signaling following acute angiogenic gene transcription. Here, we evaluate the global mapping of VEGF-mediated dynamic transcriptional events, focusing on major histone-code profiles using chromatin immunoprecipitation sequencing (ChIP-seq). Remarkably, the gene loci of immediate-early angiogenic transcription factors (TFs) exclusively acquire bivalent H3K4me3-H3K27me3 double-positive histone marks after the VEGF stimulus. Moreover, NFAT-associated Pax transactivation domain-interacting protein (PTIP) directs bivalently marked TF genes transcription through a limited polymerase II running. The non-canonical polycomb1 variant PRC1.3 specifically binds to and allows the transactivation of PRC2-enriched bivalent angiogenic TFs until conventional PRC1-mediated gene silencing is achieved. Knockdown of these genes abrogates post-natal aberrant neovessel formation via the selective inhibition of indispensable bivalent angiogenic TF gene transcription. Collectively, the reported dynamic histone mark landscape may uncover the importance of immediate-early genes and the development of advanced anti-angiogenic strategies. [Display omitted] • Specific bivalent gene body signature regulates VEGF-responsive angiogenic acute TFs • Non-canonical PRC1.3 transiently transactivates PRC2-enriched angiogenic genes • VEGF-NFAT-associated epigenome modifier PTIP directs NFAT-targeted gene activation • Reductions in PRC1.3 or PTIP lead to impaired postnatal angiogenesis Kanki et al. demonstrate that angiogenesis-essential immediate-early genes are silent with canonical PRC-brake in inert endothelium. In a short time, VEGF unlocks the transcription of these genes through bivalent H3K4me3-H3K27me3 histone marks on the gene loci with PTIP/NFAT, MLL3/4, and non-canonical PRC1.3 accumulation. [ABSTRACT FROM AUTHOR]