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studies have found corroboration for this bias. One study focused on a
protein-protein network regulated by miR-204, a miRNA that was shown
to function as a tumor suppressor (
Lee
et al
., 2010
). Within the network,
two distinct modules (cell adhesion and cell cycle) are found, and each
module is connected to the other via bottlenecks. Within each module,
miR-204 preferentially targets mRNAs encoding hub and bottleneck pro-
teins (
Lee
et al
., 2010
). Interestingly, miR-204 suppression significantly
augments cell cycle and extracellular matrix remodeling
in vitro
and
in vivo
(
Lee
et al
., 2010
). Another study showed that several miRNAs are predicted
as regulators for various modules of tightly coexpressed genes (
Bonnet
et al
.,
2010
). miR-200a is the top regulator of a small module of nine genes that is
part of a larger network, such that this miRNA regulates the module via the
TF ZEB1. Interestingly, this module is most likely involved in epithelial
homeostasis, and its dysregulation could contribute to the malignant process
in cancer cells (
Bonnet
et al
., 2010
).
A second modularity-related property of miRNAs is that they cotarget
molecules belonging to the same module (
Fig. 9.4
B). Cotargeting occurs by
subsets of either unrelated miRNAs or a particular miRNA family. For
example, there is pervasive regulation of several related transcription repres-
sors that function in the Notch signaling network by three different classes
of miRNAs that each recognizes a similar seed sequence in their targets
(
Lai
et al
., 2005
). Further support for this property has come from compu-
tational studies.
Basu
et al.
(2011)
found that coregulated targets tend to
be organized within network modules. More than half of modules with
prevalent coregulated targets are not simply explained by seed similarity
(
Mookherjee
et al
., 2009b
). Two other computational analyses showed that
cotargeted genes and their interacting neighbors jointly show significantly
higher modularity, and clustered miRNAs jointly regulate proteins in close
proximity within a protein-protein interaction network (
Hsu
et al
., 2008
;
Yuan
et al
., 2009
). These analyses support the notion that coregulation of
targets within modules is a prevalent phenomenon.
As factors belonging to a module are corepressed, modular regulation
increases the redundancy of the cotarget network, making it robust to the
individual loss or rewiring of some of the miRNAs. Consistent with this
feature, miRNAs are individually not essential (
Miska
et al
., 2007
). The
concept of miRNA regulative modularity is also in accordance with
observations that relate specific miRNAs to cancer development. Up- or
downregulation of miRNAs repressing particular modules is associated
with loss of robustness that is linked with cancer progression
(
Bandyopadhyay
et al
., 2010
). For example, five miRNAs (miR-19b,
miR-20a, miR-26a, miR-92, and miR-223), which are capable of pro-
moting T-cell acute lymphoblastic leukemia (T-ALL) in a mouse model,
account for the majority of miRNA expression in human T-ALL. This
small set of miRNAs is responsible for the cooperative suppression of
