Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
J Virol. 2012 Dec;86(23):12741-59. doi: 10.1128/JVI.01655-12. Epub 2012 Sep 12.
In herpes simplex virus 1 (HSV-1), binding clusters enriched in CTCF during latency have been previously identified. We hypothesized that CTCF binding to CTCF clusters in HSV-1 would be disrupted in a reactivation event. To investigate, CTCF occupation of three CTCF binding clusters in HSV-1 was analyzed following sodium butyrate (NaB)- and explant-induced reactivation in the mouse. Our data show that the CTCF domains positioned within the HSV-1 genome, specifically around the latency-associated transcript (LAT) and ICP0 and ICP4 regions of the genome, lose CTCF occupancy following the application of reactivation stimuli in wild-type virus. We also found that CTCF binding clusters upstream of the ICP0 and ICP4 promoters both function as classical insulators capable of acting as enhancer blockers of the LAT enhancer. Finally, our results suggest that CTCF occupation of domains in HSV-1 may be differentially regulated both during latency and at early times following reactivation by the presence of lytic transcripts and further implicate epigenetic regulation of HSV-1 as a critical component of the latency-reactivation transition.
在单纯疱疹病毒 1（HSV-1）中，先前已经鉴定出在潜伏期富含 CTCF 的结合簇。我们假设，在重新激活事件中，HSV-1 中的 CTCF 与 CTCF 簇的结合将被破坏。为了研究这一点，在小鼠中用丁酸钠（NaB）和外植体诱导重新激活后，分析了 HSV-1 中三个 CTCF 结合簇的 CTCF 占据情况。我们的数据表明，位于 HSV-1 基因组内的 CTCF 结构域，特别是在潜伏相关转录物（LAT）和基因组的 ICP0 和 ICP4 区域周围，在野生型病毒应用重新激活刺激后失去 CTCF 占据。我们还发现，ICP0 和 ICP4 启动子上游的 CTCF 结合簇都作为经典的绝缘子起作用，能够充当 LAT 增强子的增强子阻断剂。最后，我们的结果表明，HSV-1 中结构域的 CTCF 占据可能在潜伏期和重新激活后早期通过裂解转录本的存在而受到差异调节，并进一步表明 HSV-1 的表观遗传调节是潜伏-重新激活转换的关键组成部分。
