Random, asynchronous, and asymmetric transcriptional activity of enhancer-flanking major immediate-early genes ie1/3 and ie2 during murine cytomegalovirus latency in the lungs
Nka. Grzimek et al., Random, asynchronous, and asymmetric transcriptional activity of enhancer-flanking major immediate-early genes ie1/3 and ie2 during murine cytomegalovirus latency in the lungs, J VIROLOGY, 75(6), 2001, pp. 2692-2705
The lungs are a major organ site of cytomegalovirus (CMV) pathogenesis, lat
ency, 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 requ
ires expression of the ie1/3 transcription unit, which is driven by the imm
ediate-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 contra
st, IE1 transcripts were found to be generated focally and randomly, reflec
ting sporadic p(1/3) activity. Selective generation of IE1 transcripts impl
ies molecular control of latency operating after ie1/3 transcription initia
tion. p(1/3) is regulated by an upstream enhancer. It is widely assumed tha
t the viral transcriptional program is started by activation of the enhance
r through the binding of transcription factors. Accordingly, stochastic tra
nscription 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 combi
ned control unit p(1/3) -E-P-2. Our data are consistent,vith a stochastic n
ature of enhancer action as it is proposed by the "binary" or probability m
odel.