Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis
Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis
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二价组蛋白标记的早期基因调控对于 VEGF 响应性血管生成至关重要
DOI：
10.1016/j.celrep.2022.110332
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发表时间：
2022
期刊：
影响因子：
8.8
通讯作者：
Minami Takashi
中科院分区：
文献类型：
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作者：
Kanki Yasuharu;Muramatsu Masashi;Miyamura Yuri;Kikuchi Kenta;Higashijima Yoshiki;Nakaki Ryo;Suehiro Jun-ichi;Sasaki Yuji;Kubota Yoshiaki;Koseki Haruhiko;Morioka Hiroshi;Kodama Tatsuhiko;Nakao Mitsuyoshi;Kurotaki Daisuke;Aburatani Hiroyuki;Minami Takashi
内皮细胞（EC）的表型异质性，主要是由于他们的动态响应组织微环境。血管内皮细胞生长因子（VEGF）是最著名的血管生成因子，在急性血管生成基因转录后激活活化T细胞的钙核因子（NFAT）信号传导。在这里，我们评估了VEGF介导的动态转录事件的全球映射，重点是主要的组蛋白编码配置文件使用染色质免疫沉淀测序（ChIP-seq）。值得注意的是，立即早期血管生成转录因子（TF）的基因位点在VEGF刺激后仅获得二价H3 K4 me 3-H3 K27 me 3双阳性组蛋白标记。此外，NFAT相关的Pax反式激活结构域相互作用蛋白（PTIP）通过有限的聚合酶II运行指导双链标记的TF基因的转录。非典型的polycomb 1变体PRC1.3特异性结合并允许PRC 2富集的二价血管生成TF的反式激活，直到实现常规的PRC 1介导的基因沉默。这些基因的敲除通过选择性抑制不可或缺的二价血管生成TF基因转录来消除出生后异常新生血管形成。总的来说，报告的动态组蛋白标记景观可能会揭示立即早期基因和先进抗血管生成策略发展的重要性。
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.