Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells.
Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells.
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组蛋白脱乙酰基酶活性对于Hoxa9的表达和祖细胞的内皮承诺至关重要。
DOI：
10.1084/jem.20042097
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发表时间：
2005-06-06
期刊：
影响因子：
--
通讯作者：
Dimmeler S
中科院分区：
文献类型：
--
作者：
Rössig L;Urbich C;Brühl T;Dernbach E;Heeschen C;Chavakis E;Sasaki K;Aicher D;Diehl F;Seeger F;Potente M;Aicher A;Zanetta L;Dejana E;Zeiher AM;Dimmeler S
乙酰化的调节是谱系特异性基因表达的表观遗传控制的核心，并决定细胞命运的决定。我们提供的证据表明，组蛋白脱乙酰酶（HDAC）的抑制阻断成人祖细胞的内皮分化。为了确定HDAC抑制阻止内皮分化的机制，我们确定了同源框转录因子的表达，并证明HDAC抑制剂下调了HoxA 9的表达。HoxA 9在成体祖细胞的内皮分化中的因果关系参与得到以下发现的支持：HoxA 9过表达部分地挽救了由HDAC抑制剂诱导的内皮分化阻断。敲除和过表达研究表明，HoxA 9作为一个主开关，调节内皮细胞的表达，如内皮型一氧化氮合酶，VEGF-R2和VE-钙粘蛋白，并介导剪切应力诱导的内皮细胞成熟。一致地，HoxA 9缺陷型小鼠表现出较低数量的内皮祖细胞，并表现出受损的出生后新生血管形成能力诱导缺血后。因此，HoxA 9受HDAC调节，对出生后新生血管形成至关重要。
The regulation of acetylation is central for the epigenetic control of lineage-specific gene expression and determines cell fate decisions. We provide evidence that the inhibition of histone deacetylases (HDACs) blocks the endothelial differentiation of adult progenitor cells. To define the mechanisms by which HDAC inhibition prevents endothelial differentiation, we determined the expression of homeobox transcription factors and demonstrated that HoxA9 expression is down-regulated by HDAC inhibitors. The causal involvement of HoxA9 in the endothelial differentiation of adult progenitor cells is supported by the finding that HoxA9 overexpression partially rescued the endothelial differentiation blockade induced by HDAC inhibitors. Knockdown and overexpression studies revealed that HoxA9 acts as a master switch to regulate the expression of prototypical endothelial-committed genes such as endothelial nitric oxide synthase, VEGF-R2, and VE-cadherin, and mediates the shear stress–induced maturation of endothelial cells. Consistently, HoxA9-deficient mice exhibited lower numbers of endothelial progenitor cells and showed an impaired postnatal neovascularization capacity after the induction of ischemia. Thus, HoxA9 is regulated by HDACs and is critical for postnatal neovascularization.
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