Random, asynchronous, and asymmetric transcriptional activity of enhancer-flanking major immediate-early genes ie1/3 and ie2 during murine cytomegalovirus latency in the lungs
Random, asynchronous, and asymmetric transcriptional activity of enhancer-flanking major immediate-early genes ie1/3 and ie2 during murine cytomegalovirus latency in the lungs
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DOI：
10.1128/jvi.75.6.2692-2705.2001
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发表时间：
2001-03-01
影响因子：
5.4
通讯作者：
Reddehase, MJ
中科院分区：
文献类型：
--
作者：
Grzimek, NKA;Dreis, D;Reddehase, MJ
肺是巨细胞病毒（CMV）发病、潜伏和复发的主要器官部位。先前关于鼠CMV潜伏期的工作已经记录了在生产性感染消退后病毒基因组在肺中的高负荷和均匀分布。生产周期的启动需要ie 1/3转录单位的表达，其由立即早期（IE）启动子p（1/3）驱动，并通过差异剪接产生IE 1和IE 3转录物。潜伏期在分子上由指定必需的反式激活蛋白IE 3的IE 3转录物的缺乏来定义。与此相反，IE 1转录本被发现产生局灶性和随机，反映零星的p（1/3）活动。IE 1转录本的选择性生成意味着在IE 1/3转录起始后操作的潜伏期的分子控制。p（1/3）受上游增强子调控。人们普遍认为，病毒转录程序是通过转录因子的结合激活增强子而启动的。因此，潜伏期内的随机转录可能反映了内在转录因子的“噪音”活性激活增强子的情况。除了ie 1/3，增强子控制基因ie 2，它有自己的启动子，P-2，并以相反的方向转录。我们在这里展示了ie 2在潜伏期也是随机转录的。然而，值得注意的是，发现ie 1和ie 2是独立表达的。我们从这一发现中推断，主要IE基因的表达是通过组合控制单元p（1/3）-E-P-2不对称和异步调节的。我们的数据是一致的，Vith增强子作用的随机性，因为它是由“二进制”或概率模型提出的。
The lungs are a major organ site of cytomegalovirus (CMV) pathogenesis, latency, and recurrence. Previous work on murine CMV latency has documented a high load and an even distribution of viral genomes in the lungs after the resolution of productive infection. Initiation of the productive cycle requires expression of the ie1/3 transcription unit, which is driven by the immediate-early (IE) promoter p(1/3) and generates IE1 and IE3 transcripts by differential splicing. Latency is molecularly defined by the absence of IE3 transcripts specifying the essential transactivator protein IE3. In contrast, IE1 transcripts were found to be generated focally and randomly, reflecting sporadic p(1/3) activity. Selective generation of IE1 transcripts implies molecular control of latency operating after ie1/3 transcription initiation. p(1/3) is regulated by an upstream enhancer. It is widely assumed that the viral transcriptional program is started by activation of the enhancer through the binding of transcription factors. Accordingly, stochastic transcription during latency might reflect episodes of enhancer activation by the "noise" activity of intrinsic transcription factors. In addition to ie1/3, the enhancer controls gene ie2, which has its own promoter, P-2, and is transcribed in opposite direction. We show here that ie2 is also randomly transcribed during latency. Notably, however, iel and ie2 were found to be expressed independently. We infer from this finding that expression of the major IE genes is regulated asymmetrically and asynchronously via the combined control unit p(1/3) -E-P-2. Our data are consistent,vith a stochastic nature of enhancer action as it is proposed by the "binary" or probability model.