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
Affiliations
Yasuharu Kanki
Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan; Laboratory of Sports Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaragi 305-8574, Japan
Masashi Muramatsu
Division of Molecular and Vascular Biology, IRDA, Kumamoto University, 2-2-1 Honjo Chuo-ku, Kumamoto 860-0811, Japan
Yuri Miyamura
Division of Molecular and Vascular Biology, IRDA, Kumamoto University, 2-2-1 Honjo Chuo-ku, Kumamoto 860-0811, Japan
Kenta Kikuchi
Laboratory of Chromatin Organization in Immune Cell Development, IRCMS, Kumamoto University, Kumamoto 860-0811, Japan
Yoshiki Higashijima
Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan; Department of Bioinformational Pharmacology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Ryo Nakaki
Division of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, Japan
Jun-ichi Suehiro
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo 181-0004, Japan
Yuji Sasaki
Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan; Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan
Yoshiaki Kubota
Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan
Haruhiko Koseki
Laboratories of Developmental Genetics, RIKEN, Yokohama, Kanagawa 230-0045, Japan
Hiroshi Morioka
Department of Life Science, Kumamoto University, Kumamoto 862-0973, Japan
Tatsuhiko Kodama
Division of Systems Biology, RCAST, The University of Tokyo, Tokyo 153-8904, Japan
Mitsuyoshi Nakao
Departments of Medical Cell Biology, IMEG, Kumamoto University, Kumamoto 860-0811, Japan
Daisuke Kurotaki
Laboratory of Chromatin Organization in Immune Cell Development, IRCMS, Kumamoto University, Kumamoto 860-0811, Japan
Hiroyuki Aburatani
Division of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, Japan
Takashi Minami
Division of Molecular and Vascular Biology, IRDA, Kumamoto University, 2-2-1 Honjo Chuo-ku, Kumamoto 860-0811, Japan; Corresponding author
Summary: 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.
