MEF2 transcription factors are key regulators of sprouting angiogenesis.
MEF2 transcription factors are key regulators of sprouting angiogenesis.
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DOI：
10.1101/gad.290619.116
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发表时间：
2016-10-15
影响因子：
10.5
通讯作者：
De Val S
中科院分区：
文献类型：
--
作者：
Sacilotto N;Chouliaras KM;Nikitenko LL;Lu YW;Fritzsche M;Wallace MD;Nornes S;García-Moreno F;Payne S;Bridges E;Liu K;Biggs D;Ratnayaka I;Herbert SP;Molnár Z;Harris AL;Davies B;Bond GL;Bou-Gharios G;Schwarz JJ;De Val S
在这项研究中，Saccilotto 等人。研究了血管生成过程中促血管生成信号和下游基因表达之间的分子联系。通过表征 Dll4 增强子在血管生成前沿引导内皮细胞表达，作者确定 MEF2 转录因子是 VEGFA 直接下游萌芽血管生成的关键调节因子。血管生成是现有血管形成新血管的基本过程，取决于内皮特定区室中精确的空间和时间基因表达。然而，促血管生成信号和下游基因表达之间的分子联系仍不清楚。在萌芽血管生成过程中，内皮细胞规范化为导致新血管萌芽的尖端细胞，由血管内皮生长因子 A (VEGFA) 和 Delta 样配体 4 (Dll4)/Notch 信号传导协调，并且需要高水平的 Notch 配体 DLL4。在这里，我们确定 MEF2 转录因子是 VEGFA 直接下游的发芽血管生成的关键调节因子。通过对在血管生成前沿引导内皮细胞表达的 Dll4 增强子进行表征，我们发现 MEF2 因子直接转录激活 Dll4 和许多其他关键基因的表达，这些基因在生理和肿瘤血管化的萌芽血管生成过程中上调。与 ETS 介导的调节不同，MEF2 结合基序并非普遍存在于所有内皮基因增强子和启动子中，而是在与萌芽血管生成相关的基因周围过度表达。 MEF2靶基因激活与VEGFA诱导的抑制性组蛋白脱乙酰酶的释放以及组蛋白乙酰转移酶EP300同时募集到MEF2靶基因调控元件直接相关，从而建立MEF2因子作为血管生成过程中VEGFA信号传导的转录效应子。
In this study, Saccilotto et al. investigated the molecular connection between proangiogenic signals and downstream gene expression during angiogenesis. By characterizing a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, the authors identified MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA. Angiogenesis, the fundamental process by which new blood vessels form from existing ones, depends on precise spatial and temporal gene expression within specific compartments of the endothelium. However, the molecular links between proangiogenic signals and downstream gene expression remain unclear. During sprouting angiogenesis, the specification of endothelial cells into the tip cells that lead new blood vessel sprouts is coordinated by vascular endothelial growth factor A (VEGFA) and Delta-like ligand 4 (Dll4)/Notch signaling and requires high levels of Notch ligand DLL4. Here, we identify MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA. Through the characterization of a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, we found that MEF2 factors directly transcriptionally activate the expression of Dll4 and many other key genes up-regulated during sprouting angiogenesis in both physiological and tumor vascularization. Unlike ETS-mediated regulation, MEF2-binding motifs are not ubiquitous to all endothelial gene enhancers and promoters but are instead overrepresented around genes associated with sprouting angiogenesis. MEF2 target gene activation is directly linked to VEGFA-induced release of repressive histone deacetylases and concurrent recruitment of the histone acetyltransferase EP300 to MEF2 target gene regulatory elements, thus establishing MEF2 factors as the transcriptional effectors of VEGFA signaling during angiogenesis.
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