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首页> 外文期刊>MBio >Kinetics of Facultative Heterochromatin and Polycomb Group Protein Association with the Herpes Simplex Viral Genome during Establishment of Latent Infection
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Kinetics of Facultative Heterochromatin and Polycomb Group Protein Association with the Herpes Simplex Viral Genome during Establishment of Latent Infection

机译：建立潜伏感染过程中兼并异染色质和多梳子组蛋白与单纯疱疹病毒基因组的动力学。

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The herpes simplex virus (HSV) genome is associated with heterochromatic histone modifications, including trimethylation of the lysine 27 residue of histone H3 (H3K27me3), during latent infection of neurons. Here we have examined the kinetics of general chromatin and H3K27me3 association with the viral genome during establishment of latent infection. Using both wild-type virus and a mutant virus that is unable to undergo replication in neurons, we found that histone H3 associates with viral gene promoters by 7?days postinfection (dpi). Levels of H3K27me3 were low at 7 dpi but increased dramatically by 14 dpi. Hence, general chromatin association and/or other factors may play a key role(s) in the initial silencing of lytic genes, and H3K27me3 may play a role in further suppression of the genome and/or the maintenance of latency. A component of Polycomb repressive complex 2 (PRC2), which mediates the addition of K27me3 to histone H3 (Suz12), was also recruited by 14 dpi. We have shown previously that the levels of H3K27me3 during latent infection are increased in the presence of the latency-associated transcript (LAT). However, the initial targeting of PRC2 was not found to be dependent on the LAT. We found that a component of the PRC1 complex (Bmi1), which binds to H3K27me3, was not enriched at promoters found previously to be enriched for H3K27me3. Our results are consistent with (i) chromatinization of viral DNA or other mechanisms causing the initial silencing of HSV lytic genes and (ii) facultative heterochromatin maintaining that silencing during latent infection of neurons. >IMPORTANCE The human pathogen herpes simplex virus (HSV) hides for the lifetime of the host in peripheral neurons. The mechanism by which HSV is able to shut off its gene expression and persist in neurons is not known. Here we show that the HSV DNA first associates with histone H3, with later recruitment of Polycomb repressor complex 2 (PRC2) and trimethylation of the lysine 27 residue of histone H3 (H3K27me3), a modification associated with heterochromatin. This work indicates that the initial silencing of HSV gene expression is not correlated with enrichment of H3K27me3 and that PRC2 may be recruited to already-silenced genes to further silence gene expression and/or maintain gene silencing. We demonstrate that recruitment of PRC2 is not dependent upon expression of the noncoding HSV latency-associated transcripts, indicating the presence of unknown triggers for PRC2 recruitment during the establishment of latent infection.
机译：单纯疱疹病毒（HSV）基因组与潜在的神经元潜在感染过程中的异色组蛋白修饰有关，包括组蛋白H3（H3K27me3）的赖氨酸27残基的三甲基化。在这里，我们检查了潜伏感染建立期间一般染色质和H3K27me3与病毒基因组的动力学关系。使用野生型病毒和无法在神经元中复制的突变病毒，我们发现组蛋白H3在感染后7天（dpi）与病毒基因启动子结合。 H3K27me3的水平在7 dpi时较低，但显着增加了14 dpi。因此，一般的染色质结合和/或其他因素可能在裂解基因的初始沉默中起关键作用，而H3K27me3可能在进一步抑制基因组和/或维持潜伏期中起作用。还通过14 dpi募集了Polycomb阻抑复合物2（PRC2）的一个成分，该成分介导将K27me3添加到组蛋白H3（Suz12）中。先前我们已经表明，潜伏期相关转录本（LAT）的存在下潜伏感染期间H3K27me3的水平增加。但是，未发现PRC2的初始目标取决于LAT。我们发现，与H3K27me3结合的PRC1复合物（Bmi1）的一个成分在之前发现富含H3K27me3的启动子上并未富集。我们的结果与（i）病毒DNA染色质染色或导致HSV裂解基因最初沉默的其他机制以及（ii）兼性异染色质在潜在感染神经元期间保持沉默有关。 >重要：人类病原体单纯疱疹病毒（HSV）在宿主的终生神经元中隐藏。 HSV能够关闭其基因表达并在神经元中持续存在的机制尚不清楚。在这里，我们显示HSV DNA首先与组蛋白H3相关，随后募集了Polycomb阻遏物复合物2（PRC2）和组蛋白H3（H3K27me3）的赖氨酸27残基的三甲基化，这是与异染色质相关的修饰。这项工作表明，HSV基因表达的最初沉默与H3K27me3的富集无关，PRC2可能被募集到已经沉默的基因以进一步沉默基因表达和/或维持基因沉默。我们证明，PRC2的募集并不依赖于非编码HSV潜伏期相关转录本的表达，这表明在潜伏感染建立期间存在未知的PRC2募集触发因素。

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