Biology Reference
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targeting multiple genes involved in specific pathways. For instance, miR-
181a represses several phosphatases in developing T lymphocytes (
Li
et al
.,
2007
). miR-125 family members in hematopoietic stem cells (HSCs)
repress many targets with roles in apoptosis and cell differentiation (
Guo
et al
., 2010
;
Ooi
et al
., 2010
). miR-146a has been shown to dampen the
inflammatory response by targeting Irak1, Traf6, and Stat1 (
Lu
et al
., 2010
;
Taganov
et al
., 2006
). However, other reports have found that single
miRNA targets in particular cells can play dominant roles. For instance,
repression of cMyb by miR-150 and FoxP1 by miR-34a are both important
for proper B cell development (
Rao
et al
., 2010
;
Xiao
et al
., 2007
).
A significant part of miR-223 function in myeloid cells involves targeting
of Mef2c (
Johnnidis
et al
., 2008
). Thus, different gene regulatory strategies
involving miRNAs and their targets have evolved, with some consisting of
multiple targets that impact a specific pathway and others utilizing only a
single target.
Some mRNAs possess multiple binding sites for different miRNAs
within their 3
0
UTRs. Such an array of target sites suggests that miRNAs
might work collaboratively to repress the expression of certain genes. For
instance, the 3
0
UTRs of Mtpn and p21Cip1 contain many conserved
miRNA binding sites, and greater repression of their expression is observed
in response to multiple miRNAs compared to any one miRNA alone (
Krek
et al
., 2005
;
Wu
et al
., 2010
). These studies indicate that in some cases,
alterations in certain miRNAs should be studied in the context of changes
in other relevant miRNAs in order to fully appreciate the extent of collab-
orative miRNA control.
2.4. MicroRNAs and aging
Interestingly, some of the phenotypes that have been observed in miRNA-
deficient mice take long periods of time to develop. For instance, knockouts
of either miR-15a/16-1 or miR-146a in mice suffer from hematopoieti-
cally derived tumors, but these are only detectable after at least 1year of age
(
Boldin
et al
., 2011; Klein
et al
., 2010
). miR-155
Tregs exhibit a
competitive disadvantage versus wild-type Tregs only after more than 3
months of bone marrow reconstitution (
Lu
et al
., 2009
). These delayed
phenotypes, which are preceded by long periods of unapparent phenotypic
effects, suggest that relatively small changes in target gene expression can
“build up” over time and eventually result in distinct hematopoietic con-
sequences. These mutational scenarios imply that normally miRNAs ensure
that the hematopoietic system operates with high fidelity over long periods
of time. It points to an important role for miRNAs in the aging process and
suggests that these ncRNAs may be of particular significance in the biology
of organisms with longer life spans.
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