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 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.
摘要:
内皮细胞(ECs)是表型异质性的,主要是由于它们对组织微环境的动态响应。血管内皮细胞生长因子(VEGF),最著名的血管生成因子,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。这里,我们评估了VEGF介导的动态转录事件的全局定位,使用染色质免疫沉淀测序(ChIP-seq)专注于主要的组蛋白代码谱。值得注意的是,VEGF刺激后,立即早期血管生成转录因子(TFs)的基因位点仅获得二价H3K4me3-H3K27me3组蛋白标记.此外,NFAT相关的Pax反式激活域相互作用蛋白(PTIP)通过有限的聚合酶II运行指导二价标记的TF基因转录。非规范polycob1变体PRC1.3特异性结合并允许富含PRC2的二价血管生成TF的反式激活,直到实现常规PRC1介导的基因沉默。这些基因的敲除通过选择性抑制必不可少的二价血管生成TF基因转录来消除出生后异常新血管形成。总的来说,报道的动态组蛋白标记景观可能揭示了即时早期基因的重要性和先进的抗血管生成策略的发展.