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

Yasuharu Kanki, Masashi Muramatsu, Yuri Miyamura, Kenta Kikuchi, Yoshiki Higashijima, Ryo Nakaki, Jun ichi Suehiro, Yuji Sasaki, Yoshiaki Kubota, Haruhiko Koseki, Hiroshi Morioka, Tatsuhiko Kodama, Mitsuyoshi Nakao, Daisuke Kurotaki, Hiroyuki Aburatani, Takashi Minami

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


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.

Original languageEnglish
Article number110332
JournalCell Reports
Issue number6
Publication statusPublished - 2022 Feb 8


  • ChIP-seq
  • NFAT, transcription
  • PTIP
  • VEGF
  • angiogenesis
  • bivalent histone marks
  • endothelial cells
  • immediate-early genes
  • noncanonical polycomb

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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