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首页> 外文期刊>BMC Neuroscience >Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis
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Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis

机译：组蛋白H4脱乙酰化在神经元凋亡期间的早期基因沉默中起关键作用

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Background Silencing of normal gene expression occurs early in the apoptosis of neurons, well before the cell is committed to the death pathway, and has been extensively characterized in injured retinal ganglion cells. The causative mechanism of this widespread change in gene expression is unknown. We investigated whether an epigenetic change in active chromatin, specifically histone H4 deacetylation, was an underlying mechanism of gene silencing in apoptotic retinal ganglion cells (RGCs) following an acute injury to the optic nerve. Results Histone deacetylase 3 (HDAC3) translocates to the nuclei of dying cells shortly after lesion of the optic nerve and is associated with an increase in nuclear HDAC activity and widespread histone deacetylation. H4 in promoters of representative genes was rapidly and indiscriminately deacetylated, regardless of the gene examined. As apoptosis progressed, H4 of silenced genes remained deacetylated, while H4 of newly activated genes regained, or even increased, its acetylated state. Inhibition of retinal HDAC activity with trichostatin A (TSA) was able to both preserve the expression of a representative RGC-specific gene and attenuate cell loss in response to optic nerve damage. Conclusions These data indicate that histone deacetylation plays a central role in transcriptional dysregulation in dying RGCs. The data also suggests that HDAC3, in particular, may feature heavily in apoptotic gene silencing.
机译：背景技术正常基因表达的沉默发生在神经元凋亡的早期，即在细胞进入死亡通路之前，并且已在受损的视网膜神经节细胞中得到广泛表征。基因表达这种广泛变化的原因机制尚不清楚。我们调查了活性染色质的表观遗传变化，特别是组蛋白H4脱乙酰化，是否是视神经急性损伤后凋亡的视网膜神经节细胞（RGC）中基因沉默的潜在机制。结果组蛋白脱乙酰基酶3（HDAC3）在视神经病变后不久转移到垂死细胞的核中，并与核HDAC活性增加和广泛的组蛋白脱乙酰化有关。无论所检查的基因如何，代表性基因启动子中的H4均被快速，不加选择地脱乙酰化。随着细胞凋亡的进行，沉默基因的H4保持脱乙酰化状态，而新激活基因的H4恢复甚至升高其乙酰化状态。曲古抑菌素A（TSA）抑制视网膜HDAC活性既可以保留代表性RGC特异性基因的表达，又可以减轻视神经损伤引起的细胞损失。结论这些数据表明，组蛋白去乙酰化在垂死的RGC中在转录失调中起着重要作用。数据还表明，特别是HDAC3可能在凋亡基因沉默中发挥重要作用。

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