Dynamic regulation of VEGF-inducible genes by an ERK/ERG/p300 transcriptional network
Dynamic regulation of VEGF-inducible genes by an ERK/ERG/p300 transcriptional network
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DOI：
10.1242/dev.146050
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发表时间：
2017-07-01
期刊：
影响因子：
4.6
通讯作者：
Wythe, Joshua D.
中科院分区：
文献类型：
--
作者：
Fish, Jason E.;Gutierrez, Manuel Cantu;Wythe, Joshua D.
在血管生成过程中激活的血管内皮生长因子（VEGF）信号下游的转录途径仍然不完全的特点。通过评估负责诱导内皮细胞中Notch配体δ样4（DLL 4）的信号，我们发现MAPK/ERK途径的激活反映了DLL 4转录的快速和动态诱导，并且该途径是DLL 4表达所需的。此外，VEGF/ERK信号传导诱导ETS转录因子ERG的磷酸化和活化，这是DLL 4诱导的先决条件。DLL 4的转录与转录共激活因子p300的ERG依赖性动态募集相一致。全基因组基因表达谱鉴定了VEGF响应和ERG依赖基因的网络，ERG染色质免疫沉淀（ChIP）-seq揭示了这些靶基因附近保守的ERG结合推定增强子元件的存在。在体外和体内进行的功能实验证实，这种基因网络需要ERK，ERG和p300活性。最后，基因组编辑和转基因方法表明，位于HLX上游的高度保守的ERG结合增强子（其编码与出芽血管生成有关的转录因子）是VEGF介导的诱导所必需的。总的来说，这些发现阐明了一种新的转录途径，有助于VEGF依赖性血管生成。
The transcriptional pathways activated downstream of vascular endothelial growth factor (VEGF) signaling during angiogenesis remain incompletely characterized. By assessing the signals responsible for induction of the Notch ligand delta-like 4 (DLL4) in endothelial cells, we find that activation of the MAPK/ERK pathway mirrors the rapid and dynamic induction of DLL4 transcription and that this pathway is required for DLL4 expression. Furthermore, VEGF/ERK signaling induces phosphorylation and activation of the ETS transcription factor ERG, a prerequisite for DLL4 induction. Transcription of DLL4 coincides with dynamic ERG-dependent recruitment of the transcriptional co-activator p300. Genome-wide gene expression profiling identified a network of VEGF-responsive and ERG-dependent genes, and ERG chromatin immunoprecipitation (ChIP)-seq revealed the presence of conserved ERG-bound putative enhancer elements near these target genes. Functional experiments performed in vitro and in vivo confirm that this network of genes requires ERK, ERG and p300 activity. Finally, genome-editing and transgenic approaches demonstrate that a highly conserved ERG-bound enhancer located upstream of HLX (which encodes a transcription factor implicated in sprouting angiogenesis) is required for its VEGF-mediated induction. Collectively, these findings elucidate a novel transcriptional pathway contributing to VEGF-dependent angiogenesis.