Biology Reference
In-Depth Information
This, again, shows the difficulty in identifying virus genes specifically
implicated in the molecular control of latency and reactivation. Mutations of any
viral gene that directly or indirectly influences the latent viral genome load can
have a phenotype in latency and reactivation. This includes genes directly involved
in viral replicative fitness and spread, but also genes involved in the immune con-
trol of virus replication and spread either by encoding an antigen or by encoding
an immunomodulatory protein. Clearly, this is not what we look upon as being a
true
latency gene
.
Bidirectional Gene Pair Architecture of the Regulatory
Major Immediate Early Locus
It is widely accepted that the MIE locus of CMVs, which includes an essential
enhancer region (Dorsch-Häsler et al. 1985; Ghazal et al. 2003; for a review, see
Meier and Stinski 2006), is a key regulatory unit that kick-starts the viral
transcriptional program in acute infection as well as in reactivation from latency
(see the chapters by G. Maul; M.F. Stinski and D.T. Petrik, this volume). An open
viral chromatin structure at the MIE locus appears to be a primary condition for
reactivation to be initiated (Bain et al. 2006; see the chapter by M. Reeves and
J. Sinclair, this volume). The MIE locus in mCMV is unique in that it is structurally
organized as a
bidirectional gene pair
. Bidirectional gene pair architecture is
defined as two neighboring genes arranged head-to-head on opposite strands of
the DNA and regulated by a shared
cis
-acting regulatory unit. It has long been
known that this organization applies to the mCMV MIE locus (Fig. 1) (for a
review see Simon et al. 2006b). Interest in this structural feature of the mCMV
MIE locus (Chatellard et al. 2007; Simon et al. 2007) results from the recent
finding that bidirectional gene pairs are common in the human genome, often
conserved among mouse orthologs and thought to provide a unique mecha-
nism of regulation for a significant number of mammalian genes, in particular
of genes involved in DNA repair (Adachi and Lieber 2002; Li et al. 2006;
Trinklein et al. 2004). That such an architecture is used by mCMV just for the
MIE locus, a locus of outstanding regulatory importance, is intriguing and
underlines the close host-relatedness of this highly host-adapted virus. In this
context, it is of interest to note that hCMV uses a bidirectional promoter
element within oriLyt, another locus with a key function in acute infection and
reactivation (Xu et al. 2004).
Recent data suggest that the mCMV MIE enhancer region is actually a
tandem of two bona fide enhancers E
1/3
and E
2
(Chatellard et al. 2007) driving
the transcription from genes
m123/M122
(
ie1/ie3
) and
m128
(
ie2
), respec-
tively, in opposite directions. Alternative splicing of the IE1/IE3 precursor
RNA leads to IE1 mRNA (coding exons 2, 3, and 4) and IE3 mRNA (coding exons
2, 3, and 5); splicing of IE2 precursor RNA leads to IE2 mRNA (coding exon 3).
