Bloom David C, Giordani Nicole V, Kwiatkowski Dacia L
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610-0266, USA.
Biochim Biophys Acta. 2010 Mar-Apr;1799(3-4):246-56. doi: 10.1016/j.bbagrm.2009.12.001. Epub 2010 Jan 4.
Like other alpha-herpesviruses, Herpes Simplex Virus Type 1 (HSV-1) possesses the ability to establish latency in sensory ganglia as a non-integrated, nucleosome-associated episome in the host cell nucleus. Transcription of the genome is limited to the Latency-Associated Transcript (LAT), while the lytic genes are maintained in a transcriptionally repressed state. This partitioning of the genome into areas of active and inactive transcription suggests epigenetic control of HSV-1 latent gene expression. During latency viral transcription is not regulated by DNA methylation but likely by post-translational histone modifications. The LAT region is the only region of the genome enriched in marks indicative of transcriptional permissiveness, specifically dimethyl H3 K4 and acetyl H3 K9, K14, while the lytic genes appear under-enriched in those same marks. In addition, facultative heterochromatin marks, specifically trimethyl H3 K27 and the histone variant macroH2A, are enriched on lytic genes during latency. The distinct epigenetic domains of the LAT and the lytic genes appear to be separated by chromatin insulators. Binding of CTCF, a protein that binds to all known vertebrate insulators, to sites within the HSV-1 genome likely prevents heterochromatic spreading and blocks enhancer activity. When the latent viral genome undergoes stress-induced reactivation, it is possible that CTCF binding and insulator function are abrogated, enabling lytic gene transcription to ensue. In this review we summarize our current understanding of latent HSV-1 epigenetic regulation as it pertains to infections in both the rabbit and mouse models. CTCF insulator function and regulation of histone tail modifications will be discussed. We will also present a current model of how the latent genome is carefully controlled at the epigenetic level and how stress-induced changes to it may trigger reactivation.
与其他α-疱疹病毒一样，单纯疱疹病毒1型（HSV-1）能够在感觉神经节中建立潜伏状态，以非整合的、与核小体相关的附加体形式存在于宿主细胞核中。基因组的转录仅限于潜伏相关转录本（LAT），而裂解基因则维持在转录抑制状态。基因组在活跃转录区和非活跃转录区的这种划分表明HSV-1潜伏基因表达存在表观遗传调控。在潜伏期间，病毒转录不受DNA甲基化调节，而可能受翻译后组蛋白修饰调节。LAT区域是基因组中唯一富含表明转录许可标记的区域，特别是二甲基化的H3 K4和乙酰化的H3 K9、K14，而裂解基因在这些相同标记中的含量似乎较低。此外，兼性异染色质标记，特别是三甲基化的H3 K27和组蛋白变体macroH2A，在潜伏期间在裂解基因上富集。LAT和裂解基因的不同表观遗传结构域似乎由染色质绝缘子分隔。CTCF是一种与所有已知脊椎动物绝缘子结合的蛋白质，它与HSV-1基因组内的位点结合可能会阻止异染色质扩散并阻断增强子活性。当潜伏的病毒基因组经历应激诱导的重新激活时，CTCF结合和绝缘子功能可能会被废除，从而使裂解基因转录得以发生。在这篇综述中，我们总结了目前对潜伏HSV-1表观遗传调控的理解，这与兔和小鼠模型中的感染有关。我们将讨论CTCF绝缘子功能和组蛋白尾部修饰的调节。我们还将提出一个当前模型，说明潜伏基因组如何在表观遗传水平上受到精确控制，以及应激诱导的变化如何触发重新激活。
