Biology Reference
In-Depth Information
several tumor suppressor factors, achieved through an overlapping and
cooperative regulation of these miRNAs (
Mavrakis
et al
., 2011
).
1.4. How do these properties affect network robustness?
Nonuniform perturbation in network activity is most keenly “felt” by
critical nodes such as hubs and bottlenecks since their extensive in-links
act to amplify any perturbation. This amplification must be dampened in
order to maintain these nodes working in synchrony with less connected
nodes that do not experience such a degree of amplification. miRNAs
weakly repress protein expression and thus are well suited to dampen hubs
or bottlenecks in times of perturbation. Another reason critical nodes are
targeted is one of impact. If a hub or bottleneck is perturbed, it has the
most impact on the network's stability. Therefore, miRNAs that dampen
such perturbation will contribute more greatly to network stability than
miRNAs that target other types of nodes. A flip side of the impact theme
is that perturbation of one section of a network is transduced most strongly
to the rest of the network by hubs and bottlenecks. Dampening the
transduced perturbation at these central nodes has both the broadest and
swiftest effect on stabilizing the entire network and achieving synchroniza-
tion. It also has the advantage of being able to respond to a wider variety of
perturbations.
The modularity of miRNA targeting is also well suited to providing
robustness. As a module is semiautonomous with distinctive biochemical
properties, it specifically responds to perturbation relative to the rest of the
network. A perturbation can thus be contained within a module by exact
and coordinated regulation of the handful of nodes acting within a module
or by regulation of bottlenecks. Clearly, miRNAs with tunable and parallel
(redundant) regulatory capabilities are well suited to dampen perturbations
within a module. This activity then would help prevent destabilization of
the remainder of the network.
The pattern of miRNA regulation in signaling networks further
provides robustness. Preferential regulation of the most downstream nodes
in signal flow facilitates rapid responses with minimal lag when upstream
nodes are perturbed. This pattern of regulation also makes signaling
networks less prone to respond to noise resulting from signal propagation,
since amplification of upstream noise would be dampened downstream.
2. MicroRNAs and Circuits
In this section, we review how small-scale circuits can provide robust-
ness to biological processes, associating miRNA function with particular
features of networks.
