Biology Reference
In-Depth Information
Genomic arrangement has important implications for miRNA expression.
Clustering of miRNAs implies the ability to coordinate miRNA expression. It has
recently been shown that the 14 EBV
BART
miRNAs are indeed coordinately
expressed, and that expression of the
BART
miRNAs, which lie in the intron(s) of
the
BART
mRNA, was correlated with the expression of the
BART
mRNA (Cai
et al. 2006). The three
BHRF1
miRNAs are temporally and coordinately expressed
(discussed Sect. 4.1 below) predominately by the usage of alternate promoters
active in stage III EBV latency (Cai et al. 2006). All twelve KSHV miRNAs identi-
fied to date originate from a single cluster approximately 4 kb in length (Gottwein
et al. 2006). Of the 12, ten of these miRNAs are intronic, one is in the kaposin ORF,
and one is found in the 3′-UTR of the kaposin gene (Cai et al. 2005; Pfeffer et al.
2005). Transcript mapping has identified four different transcripts from which all
or only some of the KSHV miRNAs are derived (Cai and Cullen 2006). Interestingly,
rLCV and rhesus macaque rhadinovirus (RRV), primate herpesviruses that are dis-
tantly related to EBV and KSHV, respectively, possess miRNA clusters that are in
similar genomic positions (Schafer et al. 2007) .
HCMV pre-miRNAs are mostly intergenic (5) or are coded for on the anti-sense
strand of ORFs (4), while the remaining two HCMV pre-miRNAs partially overlap
known ORFs (Figs. 1, 3). The distribution of HCMV miRNAs has likely implica-
tions for their transcriptional regulation. The clustering of other herpesvirus miR-
NAs implies their coordinated expression under the control of a master regulatory
sequence, while the broad distribution of HCMV miRNAs across the genome
implies different mechanisms of transcriptional control. Most likely, each spatially
isolated miRNA may have its own regulatory sequence dedicated solely to its
transcriptional control and would be operating independently of other miRNAs.
Alternatively, expression of HCMV miRNAs may also be coordinated with each
other, with an enhancer-like element coordinating expression of multiple miRNAs
found far apart on the genome. It will be important to identify the promoter
elements and signaling events associated with expression of HCMV miRNAs.
HCMV miRNA Expression
Owing to the complex life cycle exhibited by HCMV, multiple issues regarding the
expression of viral miRNAs should be addressed, including expression kinetics,
miRNA expression in different cell types and latent vs lytic expression.
Kinetic Classes of HCMV miRNAs
Herpesvirus lytic gene expression is characterized by cascade regulation
(Roizman 2001; Roizman and Pellett 2007). As such, there are three kinetic
classes of HCMV genes characterized by their dependence on viral protein syn-
thesis and/or viral genome replication. Viral genes that are expressed prior to de
