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

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

doi:10.1016/j.celrep.2022.110332

Abstract

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 Tcells (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.

Highlights

The endothelium is a highly malleable cell layer that constantly senses and reacts to changes in the extracellular microenvironment
Vascular endothelial cell growth factor (VEGF) induces bivalent histone modifications in the gene bodies of angiogenic acute transcription factors (TFs) We have previously reported that VEGF primes and maintains the differentiation of pluripotent embryonic stem cells (ESCs) into Endothelial cells (ECs)
Class I genes involved acute TFs that are predominantly induced by nuclear factor of activated T cell (NFAT), as per the genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis (Figure S1A) (Suehiro et al, 2014)

Summary

Introduction

The endothelium is a highly malleable cell layer that constantly senses and reacts to changes in the extracellular microenvironment. Vascular endothelial cell growth factor (VEGF) is an endothelial cell (EC)-specific growth factor that modulates gene transcription, resulting in cell proliferation, migration, and successive angiogenesis. Such angiogenesis control is essential for the maintenance of homeostasis in the body. Over-sustained, or temporally misplaced angiogenesis may lead to vasculopathy, which involves inflammation, hypercoagulability, tumor growth, and metastasis (Apte et al, 2019; Minami and Aird, 2005). Epigenetics has recently been recognized as the chromatinbased study of how cells control gene activity without changing the DNA sequence. Gene transcription is regulated by the epigenetic status (ENCODE Project Consortium, 2012). There are six H3K4 lysine methyltransferases involving a COMPASS and COMPASS-like

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