Chromatin dynamics and the transcriptional competence of HSV-1 genomes during lytic infections
Chromatin dynamics and the transcriptional competence of HSV-1 genomes during lytic infections
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DOI：
10.1371/journal.ppat.1008076
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发表时间：
2019-11-01
期刊：
影响因子：
6.7
通讯作者：
Schang, Luis M.
中科院分区：
文献类型：
--
作者：
Hu, MiYao;Depledge, Daniel P.;Schang, Luis M.
在单纯疱疹病毒1型（HSV-1）潜伏感染期间，病毒转录受到限制，基因组主要维持在沉默的染色质中，而在裂解感染的细胞中，所有病毒基因都被转录，基因组被动态染色质化。病毒染色质中的组蛋白在裂解性感染的早期具有沉默染色质的标记，或在后期具有活跃转录的标记。病毒体蛋白VP 16通过将转录激活因子和染色质重塑因子募集到它们的启动子来激活立即早期（IE）基因的转录。两种IE蛋白，ICP 0和ICP 4，调节染色质表观遗传学，然后激活早期和晚期基因的转录。虽然染色质参与HSV转录的激活机制，但其确切作用尚未完全了解。在细胞基因组中，染色质动力学通常调节转录能力，而启动子特异性转录因子决定转录活性。在此，连续消化的HSV-1染色质的生物物理分级分离，随后进行短读深测序，表明细胞核HSV-1 DNA具有与无蛋白或纯化的HSV-1 DNA不同的生物物理性质。感染细胞中的整个HSV-1基因组同样可获得。在任何给定条件下，转录或非转录基因的可及性没有差异，并且每个基因在最易及最难的染色质中完全取样。然而，HSV-1基因组在广义或限制性转录的条件下分级不同。当HSV-1转录活跃时，约1/3的HSV-1 DNA（包括完全取样的基因）分解为最易接近的染色质，但在限制HSV-1转录的条件下，这种富集降低至仅3%。限制可及性的短序列将具有不同转录水平的基因分开。因此，染色质动态提供了对HSV-1转录的第一水平调节，决定了裂解感染期间基因组的转录能力，而单个基因的转录则最有可能被特定的转录因子激活。此外，转录到不同水平的基因被具有有限可及性的短序列分开。
During latent infections with herpes simplex virus 1 (HSV-1), viral transcription is restricted and the genomes are mostly maintained in silenced chromatin, whereas in lytically infected cells all viral genes are transcribed and the genomes are dynamically chromatinized. Histones in the viral chromatin bear markers of silenced chromatin at early times in lytic infection or of active transcription at later times. The virion protein VP16 activates transcription of the immediate-early (IE) genes by recruiting transcription activators and chromatin remodelers to their promoters. Two IE proteins, ICP0 and ICP4 which modulate chromatin epigenetics, then activate transcription of early and late genes. Although chromatin is involved in the mechanism of activation of HSV- transcription, its precise role is not entirely understood. In the cellular genome, chromatin dynamics often modulate transcription competence whereas promoter-specific transcription factors determine transcription activity. Here, biophysical fractionation of serially digested HSV-1 chromatin followed by short-read deep sequencing indicates that nuclear HSV-1 DNA has different biophysical properties than protein-free or encapsidated HSV-1 DNA. The entire HSV-1 genomes in infected cells were equally accessible. The accessibility of transcribed or non-transcribed genes under any given condition did not differ, and each gene was entirely sampled in both the most and least accessible chromatin. However, HSV-1 genomes fractionated differently under conditions of generalized or restricted transcription. Approximately 1/3 of the HSV-1 DNA including fully sampled genes resolved to the most accessible chromatin when HSV-1 transcription was active, but such enrichment was reduced to only 3% under conditions of restricted HSV-1 transcription. Short sequences of restricted accessibility separated genes with different transcription levels. Chromatin dynamics thus provide a first level of regulation on HSV-1 transcription, dictating the transcriptional competency of the genomes during lytic infections, whereas the transcription of individual genes is then most likely activated by specific transcription factors. Moreover, genes transcribed to different levels are separated by short sequences with limited accessibility.