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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Abstract
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 theie1/3 transcription unit, which is driven by the immediate-early (IE) promoter P1/3 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 P1/3activity. Selective generation of IE1 transcripts implies molecular control of latency operating after ie1/3 transcription initiation. P1/3 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, P2, and is transcribed in opposite direction. We show here that ie2 is also randomly transcribed during latency. Notably, however, ie1 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 P1/3 -E-P2. Our data are consistent with a stochastic nature of enhancer action as it is proposed by the “binary” or probability model.

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