Biology Reference
In-Depth Information
miRNA-RISC can perform seems to be rather low. According to a number
of studies, miRNAs are present at a range of 10-10,000 copies per cell
(
Chen
et al
., 2005
;
Kye
et al
., 2007
). It seems unlikely that a miRNA that is
present at very low abundance will have a switch-like behavior, while those
that are present at higher concentrations have a higher probability of acting
that way. In addition, in neurons, miRNAs are distributed across the soma
and the processes as we previously discussed. So, for example, a miRNA
that is present even at 1000 copies per cell might end up at one or less copies
per dendrite, and this will have a direct impact on the type of regulatory role
that miRNA can execute.
The mode of action will also of course be dependent on the target
mRNA concentration, and so it will be important as well how many
additional targets that miRNA has. At the same cellular concentration, a
miRNA with several targets is less likely to be able to switch all of them off,
while a miRNA with one or a few targets has a higher chance of fully
repressing its target.
Importantly, the observed effect of a miRNA on its target may not be
reflective of the direct consequence of miRNA-mediated repression, but
rather it may be the result of additional interactions. In fact, this is probably
one of the main contributors to the mode of action of a miRNA given the
fact that most miRNAs form complex gene regulatory networks with their
targets. Thus, even a modest effect of a miRNA on its target can be
amplified by feedback loops to end up in mutually exclusive expression of
the two. In such a case, the miRNA could be acting as a genetic switch even
without being a strict molecular switch. These types of interactions will be
discussed in the next section.
4.2. Network motifs involving miRNAs
It is evident from a number of the examples we have explored so far that
many miRNAs regulate the expression of specific transcription factors and
that, in turn, these TFs feedback to regulate expression of the miRNAs
themselves. More directed analyses have shown that a few network motifs
that integrate transcriptional and miRNA-mediated posttranscriptional regu-
lation are overrepresented in regulatory networks in organisms ranging from
C. elegans
to humans (
Li
et al
., 2009
;
Martinez and Walhout, 2009
;
Martinez
et al
., 2008
;
Osella
et al
., 2011
;
Tsang
et al
., 2007
). Such network motifs have
been implicated not only in providing robustness and stability to genetic
programs, maintaining stable steady-state levels of the regulatory factors, but
also in providing precise transitions (temporal and spatial) in response to
external stimuli or intrinsic signals (
Alon, 2007
).
The two most recurring motifs are feedback and feedforward loops. In a
typical double-negative feedback loop, a miRNA represses a target, a TF,
which,
in turn, represses expression of the miRNA itself (
Fig. 5.2
A).
