Regulation of Angiogenesis by Histone Chaperone HIRA-mediated Incorporation of Lysine 56-acetylated Histone H3.3 at Chromatin Domains of Endothelial Genes
Regulation of Angiogenesis by Histone Chaperone HIRA-mediated Incorporation of Lysine 56-acetylated Histone H3.3 at Chromatin Domains of Endothelial Genes
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DOI：
10.1074/jbc.m110.190025
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发表时间：
2010-12-31
影响因子：
4.8
通讯作者：
Paul, Soumen
中科院分区：
文献类型：
--
作者：
Dutta, Debasree;Ray, Soma;Paul, Soumen
血管生成严重依赖于内皮细胞特异性转录机制。然而，调控染色质结构域的分子过程，从而决定关键内皮基因的转录知之甚少。在这里，我们报告说，在内皮细胞，血管生成信号介导的转录诱导Vegfr 1（血管内皮生长因子受体1）依赖于组蛋白伴侣，HIRA（组蛋白细胞周期调节缺陷的同源物A）。我们的分子分析表明，在响应血管生成信号，HIRA诱导内皮细胞和介导的掺入赖氨酸56乙酰化组蛋白H3.3（H3acK56）在染色质结构域的Vegfr 1。HIRA介导的H3acK56掺入是与内皮细胞中几种血管生成基因的转录诱导相关的一般机制。HIRA的消耗抑制H3acK56掺入和Vegfr 1和其他血管生成基因的转录诱导。我们的功能分析表明，在体内基质胶塞试验中，HIRA的耗竭消除了基质胶上的内皮网络形成并抑制了血管生成。此外，在激光诱导的脉络膜新生血管模型中的分析显示，HIRA的耗竭显著抑制新生血管形成。我们的研究结果首次揭示了组蛋白伴侣（HIRA）依赖的内皮细胞基因调控的分子机制，并表明组蛋白伴侣可能成为血管生成治疗的新靶点。
Angiogenesis is critically dependent on endothelial cell-specific transcriptional mechanisms. However, the molecular processes that regulate chromatin domains and thereby dictate transcription of key endothelial genes are poorly understood. Here, we report that, in endothelial cells, angiogenic signal-mediated transcriptional induction of Vegfr1 (vascular endothelial growth factor receptor 1) is dependent on the histone chaperone, HIRA (histone cell cycle regulation-defective homolog A). Our molecular analyses revealed that, in response to angiogenic signals, HIRA is induced in endothelial cells and mediates incorporation of lysine 56 acetylated histone H3.3 (H3acK56) at the chromatin domain of Vegfr1. HIRA-mediated incorporation of H3acK56 is a general mechanism associated with transcriptional induction of several angiogenic genes in endothelial cells. Depletion of HIRA inhibits H3acK56 incorporation and transcriptional induction of Vegfr1 and other angiogenic genes. Our functional analyses revealed that depletion of HIRA abrogates endothelial network formation on Matrigel and inhibits angiogenesis in an in vivo Matrigel plug assay. Furthermore, analysis in a laser-induced choroidal neovascularization model showed that depletion of HIRA significantly inhibits neovascularization. Our results for the first time decipher a histone chaperone (HIRA)-dependent molecular mechanism in endothelial gene regulation and indicate that histone chaperones could be new targets for angiogenesis therapy.