Reversal of Heterochromatic Silencing of Quiescent Herpes Simplex Virus Type 1 by ICP0
Reversal of Heterochromatic Silencing of Quiescent Herpes Simplex Virus Type 1 by ICP0
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DOI：
10.1128/jvi.02263-10
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发表时间：
2011-04-01
影响因子：
5.4
通讯作者：
DeLuca, Neal A.
中科院分区：
文献类型：
--
作者：
Ferenczy, Michael W.;DeLuca, Neal A.
持续潜伏的单纯疱疹病毒基因组在某种程度上被发现处于异染色质状态，这有助于减少基因表达，导致静止。我们在人成纤维细胞中使用了一个相对长期的静止感染模型，然后提供ICP0反式，以确定ICP0对病毒染色质状态的影响，因为基因表达被重新激活。ICP0的表达，即使在低水平下，也会导致静止病毒基因组上的高阶染色质结构和异染色质的减少，并且这种作用先于转录的增加。与转录激活同时，高水平的ICP0表达导致异染色质标记三甲基化H3K9的减少，组蛋白H3和H4从静止基因组中去除，以及剩余组蛋白的超乙酰化。相反，低水平的ICP0并没有明显改变病毒基因组上组蛋白的水平。这些结果表明，ICP0活性最终在多个水平上影响静止基因组的染色质结构，包括高阶染色质结构、组蛋白修饰和组蛋白缔合。此外，ICP0表达水平影响其改变染色质结构的能力，但不影响其重新激活基因表达的能力。虽然这些观察结果表明，对染色质结构的一些影响可能不是直接的，但它们也表明ICP0通过多种机制发挥其作用。
Persisting latent herpes simplex virus genomes are to some degree found in a heterochromatic state, and this contributes to reduced gene expression resulting in quiescence. We used a relatively long-term quiescent infection model in human fibroblasts, followed by provision of ICP0 in trans, to determine the effects of ICP0 on the viral chromatin state as gene expression is reactivated. Expression of ICP0, even at low levels, results in a reduction of higher-order chromatin structure and heterochromatin on quiescent viral genomes, and this effect precedes an increase in transcription. Concurrent with transcriptional activation, high levels of ICP0 expression result in the reduction of the heterochromatin mark trimethylated H3K9, removal of histones H3 and H4 from the quiescent genome, and hyperacetylation of the remaining histones. In contrast, low levels of ICP0 did not appreciably change the levels of histones on the viral genome. These results indicate that ICP0 activity ultimately affects chromatin structure of quiescent genomes at multiple levels, including higher-order chromatin structure, histone modifications, and histone association. Additionally, the level of ICP0 expression affected its ability to change chromatin structure but not to reactivate gene expression. While these observations suggest that some of the effects on chromatin structure are possibly not direct, they also suggest that ICP0 exerts its effects through multiple mechanisms.