Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation
Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation
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DOI：
10.1074/jbc.m113.489732
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发表时间：
2013-10-04
影响因子：
4.8
通讯作者：
Westendorf, Jennifer J.
中科院分区：
文献类型：
--
作者：
Dudakovic, Amel;Evans, Jared M.;Westendorf, Jennifer J.
骨骼具有显著的再生能力，但随着年龄的增长，这种能力会减弱。组蛋白脱乙酰酶抑制物(HDI)可促进成骨细胞的终末分化和细胞外基质的产生。HDI在成骨细胞中改变的表观遗传学事件可能为开发新的合成代谢疗法治疗骨质疏松症和其他低骨量疾病提供线索。为了评估高密度脂蛋白对成骨细胞表观基因组的影响，用琥珀酰苯胺异羟肟酸(SAHA)处理MC3T3细胞，并进行微阵列基因表达谱和高通量芯片序列分析。正如预期的那样，SAHA在体外诱导成骨细胞分化和基质钙化。ChIP-Seq分析显示，除了转录起始点上游的500bp外，SaHA在全基因组和差异调控基因中增加了组蛋白H4的乙酰化。通路分析表明，SAHA增加了胰岛素信号调节因子的表达，包括SLC9a3r1。SAHA减少胰岛素受体Akt和Akt底物FoxO1的磷酸化，导致FoxO1稳定。因此，SAHA诱导全基因组的H4乙酰化，调节胰岛素/Akt/FoxO1信号轴，而它在体外促进成骨细胞的终末分化。
Bone has remarkable regenerative capacity, but this ability diminishes during aging. Histone deacetylase inhibitors (HDIs) promote terminal osteoblast differentiation and extracellular matrix production in culture. The epigenetic events altered by HDIs in osteoblasts may hold clues for the development of new anabolic treatments for osteoporosis and other conditions of low bone mass. To assess how HDIs affect the epigenome of committed osteoblasts, MC3T3 cells were treated with suberoylanilide hydroxamic acid (SAHA) and subjected to microarray gene expression profiling and high-throughput ChIP-Seq analysis. As expected, SAHA induced differentiation and matrix calcification of osteoblasts in vitro. ChIP-Seq analysis revealed that SAHA increased histone H4 acetylation genome-wide and in differentially regulated genes, except for the 500 bp upstream of transcriptional start sites. Pathway analysis indicated that SAHA increased the expression of insulin signaling modulators, including Slc9a3r1. SAHA decreased phosphorylation of insulin receptor , Akt, and the Akt substrate FoxO1, resulting in FoxO1 stabilization. Thus, SAHA induces genome-wide H4 acetylation and modulates the insulin/Akt/FoxO1 signaling axis, whereas it promotes terminal osteoblast differentiation in vitro.