Prospects & Overviews
Review essays
Species-specific microRNA regulation
influences phenotypic variability
Perspectives on species-specific microRNA regulation
Eyal Mor and Noam Shomron

Phenotypic divergence among animal species may be due
in part to species-specific (SS) regulation of gene
expression by small, non-coding regulatory RNAs termed
microRNAs. This phenomenon can be modulated by
several variables. First, microRNA genes vary by their level
of conservation, many of them being SS, or unique to a
particular evolutionary lineage. Second, microRNA ex-
pression levels vary spatially and temporally in different
species. Lastly, while microRNAs bind the 30 UTR of target
genes in order to silence their expression, the binding sites
themselves are often non-conserved. The variability of the
miRNA-target paradigm between different species is thus
multifactorial, and this paradigm has only just started to
gain attention from researchers in various fields. Here we
present and discuss recent findings regarding the char-
acteristics and implications of SS microRNA regulation.
.
Keywords:
conservation; evolution; microRNA; miRNA, species-
specific
DOI 10.1002/bies.201200157
Department of Cell and Developmental Biology, Sackler Faculty of Medicine,
Tel-Aviv University, Tel-Aviv, Israel
*Corresponding author:
Noam Shomron
E-mail: nshomron@post.tau.ac.il
Abbreviations:
LS, lineage-specific; SS, species-specific.
Bioessays 35: 0000–0000,ß 2013 WILEY Periodicals, Inc.
Introduction
MicroRNAs (miRNAs) are a group of small, non-coding RNAs
that guide post-transcriptional repression of protein-coding
genes by base-pairing with the 30 untranslated region (30 UTR)
of target messenger RNAs (mRNAs) [1]. miRNAs are tran-
scribed from distinct genomic loci that mostly reside in
intergenic regions or in introns of coding genes (mRNAs) [2].
miRNA genes are often clustered [3] and are transcribed into
primary transcripts (pri-miRNA) that are processed to discrete
RNA secondary structures, the RNA precursors (pre-miRNA) of
60–70 nt. The pre-miRNAs, in turn, are processed to yield the
double-stranded mature miRNA of 20–24 nucleotides, which
is then untangled to generate the single-stranded functional
miRNA. The miRNA regulatory site is the “seed” region,
comprising bases 2–7 (6-mer) from the mature miRNA 50
end [4]. A full complementation of this region with mRNAs is
critical for regulation of the target mRNA. However, an
alternative mode of miRNA target recognition has also been
described [5–9]. miRNAs have been extensively investigated in
the past few years, and over 25,000 miRNAs, in 193 species,
are now reported, as indicated in the miRNAs registry
“miRBase” [10].
Many miRNAs belong to miRNA families [11] in which all
members possess the same seed region that is considered to
dictate redundant targeting. miRNAs control the expression of
a large proportion of mammalian genes [12]. Every miRNA is
estimated to regulate hundreds of gene targets [13] although
the repression of a few targets usually plays a physiological
role [14–16]. Similarly, each gene can be regulated by many
miRNAs [4].
Although the physiological effect of many miRNAs is
substantial, the influence of miRNAs on the expression of their
target genes is very often limited to a mild effect, sometimes
referred to as “fine tuning” [17–19].
Many miRNAs are characterized by high sequence
conservation across highly divergent species [20]. These
miRNAs have emerged as prominent regulators of a diverse
range of biological processes. The miR-124, e.g., is highly
conserved across the animal kingdom [21] and mediates
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 E. Mor and N. Shomron
neuronal differentiation [22]. Other examples of conserved
miRNAs are the p53-induced miR-34 family that induces
apoptosis, cell-cycle arrest or senescence [23–26], and the
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muscle-specific miR-133 that is essential for proper skeletal
and cardiac muscle development [27, 28].
Despite the high conservation of many miRNAs, large
proportions of the miRNAs identified in a number of animal
species are present in only one or two species that belong to a
specific evolutionary lineage (such as mice and rats; e.g.
see [29, 30]), while others are present in at least three members
of a specific evolutionary lineage (e.g. see [31, 32]). We define
these miRNAs as species-specific (SS) and evolutionary
lineage-specific (LS), respectively. These miRNAs are less
studied probably because of their low expression [33], smaller
amount of computationally predicted targets [29], and the fact
that they did not undergo stringent evolutionary selection.
Yet, recent studies have brought our attention to the
significant function of SS/LS miRNAs in various systems
(e.g. [29–31, 34–36]).
Similarly to the miRNAs themselves, some of their
predicted binding sites on the mRNAs are also non-conserved.
While predicted conserved binding sites are expected to have
a stronger regulatory effect on their target genes [17] and are
mostly chosen as leads when searching for miRNA targets
(e.g. [37]), some non-conserved miRNA binding sites have
recently been reported to have a significant functional effect
as well (e.g. [29, 38, 39]).
These variations in both the miRNAs and their binding
sites repertoire among different species are likely to be key
drivers of phenotypic differences [40] (such as in [38]). Here,
we present and discuss recent findings regarding the different
perspectives of animal SS miRNA regulation that form a
complex SS targeting paradigm.
Species-specific and evolutionary
lineage-specific microRNAs constitute a
large proportion of the miRNAs
Following the identification of a cohort of miRNAs by
experimental approaches, computational miRNA prediction
tools have used distinguishing characteristics of these tran-
scripts, including secondary structure and free energy, in the
search of novel miRNAs [41]. The completion of genome
sequencing for many species has further enabled the
identification of large sets of miRNAs in these genomes based
on conserved miRNA homologous searches [42]. Other miRNA
discovery tools utilize the conservation of the miRNAs, target
sites, while genomic searches for conserved sequences
complementary to these motifs are used to find potential
miRNA genes [41, 43].
In search for SS miRNAs for which no close homology is
known, ab initio algorithms were developed in order to
overcome the reliance on sequence similarity to known
pre-miRNAs. Among others, exploiting local information in
the training dataset was found particularly suitable for this
purpose [44].
Given that sensitivity and false-positive rates remain a
drawback of computational approaches, the development of
deep sequencing (also known as next-generation sequencing,
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Prospects & Overviews ....
NGS) technology emerged to advance miRNA discovery [45, 46].
Small RNA sequencing enables the identification of novel
miRNAs given the large amount of sequence reads generated.
These reads serve as substrates for the miRNA prediction
algorithms, which look for miRNA distinct features (e.g. see [42,
47, 48]). This technology has enabled millions of small RNAs to
be sequenced relatively inexpensively and has allowed the
identification of novel miRNAs in many species, including
those that are SS/LS. This process is not yet exhausted given the
potential use of deep sequencing machines in different cell
types and contexts [48]. Following computational and deep
sequencing-based miRNA discovery, experimental validation,
such as testing true miRNA processing, are needed to determine
the authenticity of these newly discovered miRNAs [49].
A large proportion of the miRNAs identified using
computational or deep sequencing technologies turned out
to be SS/LS. Such miRNAs were identified in a variety of
animals, including mouse [50], rat [51], and chicken [52]. Here
we focus on SS/LS miRNAs compared to miRNAs of
comprehensive conservation (Fig. 1, upper right corner).
The proportion of SS/LS miRNAs to all miRNAs in a given
species, can be quantified using the web tool miRviewer [47].
This tool aims to present the full spectrum of miRNA sequence
and structure conservation in a variety of animals, ranging from
Caenorhabditis elegans to humans. For example, 453 (54.3%) of
the 834 human miRNAs are either human-specific (130; 15.6%)
or not conserved beyond primates (323; 38.7%), and 139 (27.6%)
of the 503 mouse miRNAs are mouse-specific (excluding miRNA
paralogs, e.g. miR-34a,b,c, and identical mature miRNAs
derived from different genomic loci, e.g. miR-124-1/2). It should
be noted, however, that these human/primate and mouse-
specific miRNAs might be present in non-primate species as
well, but cannot be currently identified using miRviewer or
miRNAminer [42] miRNA search algorithms.
Thus, large proportions of miRNAs that are identified by
computational and deep sequencing technologies are SS/LS.
Most species-specific and evolutionary
lineage-specific microRNAs are
transcribed from non-conserved miRNA
genomic loci
The evolution of miRNAs is believed to be an on-going [53] and
rapid process [40]. Some suggest that the diversification of the
miRNA repertoire, which includes SS/LS miRNAs, has
increased with increasing organismal complexity [54].
Most SS/LS miRNAs’ genomic loci are found in the
corresponding species only, meaning that the miRNAs are
transcribed from SS/LS genes (Fig. 1). In other cases, the
miRNA genomic locus is conserved but the miRNA mature
form is unique to several species. One of the means by which
such SS miRNAs are generated is adenosine-to-inosine (A-to-I)
RNA editing. A-to-I editing is catalyzed by enzymes of the
ADAR family, and post-transcriptionally changes adenosine
to inosine, the latter being treated by the cell machinery
similar to guanosine [55]. A prerequisite for this process is a
double-stranded RNA (dsRNA) structure. Such dsRNAs are
formed in the miRNA maturation process, and are affected by
.... Prospects & Overviews E. Mor and N. Shomron

Figure 1. SS microRNA regulation. SS miRNA regulation can be viewed from different perspectives. First, the miRNA genetic repertoire is Review essays
variable in different species. This is primarily due to the generation of non-conserved, SS miRNA genes. The different conservation levels of
several miRNA genes across animals are shown at the upper right hand corner (image and conservation is adapted from miRviewer; http://
people.csail.mit.edu/akiezun/miRviewer). Each column represents a different animal, some are indicated at the top. A green/gray box
indicates the presence/absence of the miRNA in the corresponding animal. Examples of conserved (Con.), SS, and LS miRNAs are
presented. Other types of SS/LS miRNAs are transcribed from conserved miRNA genes, yet their mature forms are SS/LS. These can be
generated by SS/LS nucleotide polymorphisms and/or A-to-I RNA editing of double-stranded RNA structures formed in the miRNA maturation
process, i.e. pri-miRNAs or pre-miRNAs. Second, miRNA expression levels vary spatially and temporally in different species (bottom left). For
example, the expression pattern of a single miRNA in various cell types and along a developmental time course can vary between different
species. Finally, miRNA binding sites can also be non-conserved themselves, such as the TNF-a 30 UTR binding site for miR-125/351
(bottom right) at position 125–131 from the 50 end of the 30 UTR. An alignment of the miR-351/125 binding site region on the TNF-a 30 UTR
in different animals indicates its poor conservation. Each line represents a different animal. Shaded gray rectangular regions indicate the
miRNA binding sites.

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 E. Mor and N. Shomron
A-to-I editing. Some of these modifications are at the mature
miRNA seed region [55], practically creating new miRNAs with
new sets of mRNA targets, based on “seed”-associated
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computational predictions. While miRNA editing sites only
partially overlap between different species, as demonstrated
for humans and mice [55], editing of conserved miRNA seed
regions can create SS miRNAs (Fig. 1). The conserved miR-377,
e.g., can be edited in mice but not in humans [55]. In addition,
non-conserved miRNAs can be edited to further yield new
non-conserved miRNAs, as seen for miR-589, which is present
in humans but not in mice [55].
Another means of generating SS/LS miRNAs that are
transcribed from conserved genomic loci is through sequence
polymorphisms (Fig. 1), which give rise to alterations in the
pre-miRNA, mature miRNAs, and the seed region [56]. For
example, there are 37 miRNAs found specifically in mice and
rats, with the genomic loci of 36 of these being present in the
corresponding species only. The exception is miR-298, the
genomic locus of which is present in mice and rats as well as in
primates, but its mouse and rat mature forms include variations
in the seed region [29]. As a consequence, this miRNA targets a
different set of genes in mice and rats compared to primates [29].
Polymorphisms in the miRNA seed region could even be
associated with variable traits of different mice inbred strains.
This was demonstrated for a polymorphism in the miR-717
seed region, which is associated with a diverse array of traits
including behavior, blood-clinical chemistry, body weight size
and growth, and immune system. This finding suggests that
minute changes in miRNA sequences, including those that are
prevalent in the population such as SNPs, can indeed lead to
major pleiotropic effects [56].
Although the seed sequence is a key feature for
miRNA-mRNA target recognition, there are other character-
istics that assist targeting [17, 57]. It was suggested that
nucleotide substitutions in the non-seed nucleotides of
conserved miRNAs might lead to the generation of modified
target recognition and new functions for these miRNAs, albeit
their original function is retained [58]. This can be viewed as a
natural “experimental” setting, which allows miRNA se-
quence substitutions to be maintained if their function
becomes evolutionary favorable. This mechanism would be
energetically favorable as well, compared to generating and
maintaining de novo miRNAs [58]. For example, the miR-21
sequence is the same in mammals and birds, while non-seed
nucleotide variations are found in fish species [59]. The
web-tool miRviewer can be used in order to view variations in
the pre-miRNA sequence of different species, including those
in the mature miRNA form and its seed region.
The appearance of SS/LS miRNAs can thus be attributed to
several scenarios, including A-to-I RNA editing, polymor-
phisms that appeared in miRNA sequences, and the emergence
of SS/LS miRNA loci, which is the most prevalent one.
Some SS/LS miRNAs utilize existing
transcription units and gene targets
upon their emergence
Many SS/LS miRNAs are located in miRNA clusters [3] that
contain two or more miRNA genes. These clusters may have
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Prospects & Overviews ....
evolved through local duplication events [60] and were found,
e.g., in mice and rats [60], primates [61], and marsupials [62].
Other SS/LS might have emerged as a result of non-local
miRNA loci duplications. An example is miR-351, the gene of
which is found in mice and rats only. The miR-351 gene is part
of a conserved miRNA cluster but its sequence is significantly
different from that of the other members of this cluster.
miR-351 also belongs to the ancient miR-125 family [29]. Thus,
it is reasonable that miR-351 has emerged in mice and rats
through a duplication of one of the miR-125 family members,
most likely miR-125b-1, that aligns better to miR-351 than
miR-125a or miR-125b-2 (Alignment Score 188, 181, 180,
respectively; CLUSTALW sequence alignment [63]) and was
then subjected to several mutations. This is an example of a
miRNA locus duplication that leads to an expansion of miRNA
families across different species [53].
Following their emergence, the possibility of SS/LS
miRNAs to become functional depends on their expression
level and their interplay with their targets [64]. Interestingly,
some SS/LS miRNAs have emerged downstream to established
promoter-enhancer sequences, bypassing the requirement for
generating de novo transcription regulation. The mouse- and
rat-specific miR-351 for example, has utilized an existing
transcribed unit of its hosting conserved miRNA cluster for its
expression. This was shown in resting astrocytes as well as in
activated astrocytes, where an overall downregulation of the
miRNAs in this cluster is apparent [29].
Another example is the expression regulation of the
miRNA members of a mouse and rat-specific cluster located in
the intron of the Sfmbt2 gene, and referred to as Sfmbt2 cluster.
The promoter of these miRNAs is located directly upstream to
their hosting gene [65] and dictates the induction of Sfmbt2
together with its hosted miRNAs [65, 66] in nutrient depleted
conditions. One of the members of this cluster, miR-466h-5p,
e.g., is activated following glucose deprivation-induced
oxidative stress by increased acetylation in this promoter
region [65].
While many miRNAs are characterized by high sequence
conservation across highly divergent species, which reflects
the effects of purifying selection [20], mRNAs have also
undergone selective pressure in order to maintain 7-nt sites
matching miRNAs [67]. It is thus not surprising that most SS
miRNAs have many fewer conserved binding sites as
compared to conserved ones [29]. Exceptions to this are SS
miRNAs that belong to a conserved miRNA family in which all
members share their functional seed region and thus gene
targets. The mouse and rat-specific miR-351, e.g., may regulate
the genes that have developed as targets for its other, more
ancient, family members [29].
Interestingly, although SS miRNAs are not expected to
cause a wide effect upon their emergence, Zheng et al. [40]
have found that in specific cases, SS miRNAs have driven a
genome-wide impact on the 30 UTR of their corresponding
species. The authors have developed a computational method
that identifies signatures of SS miRNA binding site gain and
loss associated with miRNA acquisition. They have found
evidence for a selection of binding sites to several mouse-
specific miRNAs in the mouse genome. Many of these
mouse-specific changes correspond to miRNA members of a
single miRNA cluster, the Sfmbt2 cluster. Using a Luciferase
.... Prospects & Overviews
reporter assay, the authors have verified the functional
targeting of some of the mouse-specific 30 UTR sequence
variations indicating their genuine significance [40].
Thus, upon their emergence, some SS/LS miRNAs have
found a favorable hosting environment for their expression
while exploiting an established transcription mechanism.
Some SS/LS miRNAs have also used an existing set of targets,
while others have acquired a genome-wide influence on their
corresponding species. These characteristics of SS miRNAs
seem to have generated favorable conditions for their function
in particular species.
SS/LS miRNAs function in varied
biological processes
SS miRNAs can be regarded as non-functional or less
influential compared to conserved miRNAs given their
non-conserved or evolutionary young regulation upon their
gene targets. For example, conserved human miRNAs
were shown to be significantly more associated with
diseases compared to non-conserved human miRNAs [68].
Nevertheless, recent findings suggest a significant
function of SS/LS miRNAs in varied biological processes,
including inflammation [29], neurogenesis [34], induction of
pluripotency [35], and apoptosis [30, 31, 66]. In fact, SS
miRNAs were found to target transcription factors, which are
transacting regulatory molecules themselves, significantly
more often than expected [69]. Thus, these miRNAs are
expected to hold a pivotal role as transcription modulators in
addition to their function in post-transcriptional regulation.
Interestingly, it seems that many of the functions
identified for SS miRNAs to date, belong to SS miRNAs that
are members of a conserved family (e.g. miR-351 [29, 34, 70],
291-3p, 294, 295 [35, 71]) as expected given their relatively large
number of conserved targets. Assuming the similar targeting
pattern of all members of a miRNA family, it is intriguing to
speculate that such SS miRNAs can either act to strengthen the
function of conserved members of their family or to
compensate for their weakened function. Comparison of
miR-351 expression to its family member miR-125b that was
shown to regulate LPS-induced macrophages activation
(e.g. [72, 73]), suggests that miR-351 strengthens miR-125b
function in this context, as both miRNAs are similarly
downregulated following LPS activation of mice peritoneal
macrophages (12 hours: miR-351 0.76-fold  0.05, miR-125b
0.82  0.04) or LPS and IFN-g activation of rat RAW264.7
macrophages (12 hours: miR-351 0.75-fold  0.09, miR-125b
0.83  0.09; mean  SEM). Interestingly, both miRNAs were
also shown to have a very similar expression pattern in the
hematopoietic hierarchy [74]. On the other hand, miR-351
might compensate for miR-125b lost function in mice
astrocytes activated by LPS and IFN-g. While miR-125b is
suppressed in marmoset activated astrocytes, as in rodents
activated macrophages, it is slightly elevated in mice activated
astrocytes, where miR-351 suppression can undertake its
downregulation role [29].
Other SS miRNAs, which were recently shown to be
functional, are not members of a conserved miRNA family.
These include miRNAs that were shown as apoptosis
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E. Mor and N. Shomron
regulators, including: (i) the pro-apoptotic primate-specific
miR-637, which acts as a tumor suppressor in hepatocellular
carcinoma by disrupting Stat3 signaling [31]; (ii) the
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pro-apoptotic mouse-specific miR-466h, which targets several
anti-apoptotic genes which leads to Caspase-3/7 activation
[66]; (iii) the mouse-specific miR-709, which directly binds to
the pri-miR-15a/16-1 in the cell nucleus and prevents its
processing maturation and its pro-apoptotic role. This
anti-apoptotic function of miR-709 is inhibited by apoptotic
signals that trigger the exit of this miRNA from the
nucleus [30]. This study provides the first evidence that
miRNAs can control the biogenesis of other miRNAs by directly
targeting their primary transcripts. miR-709 was also shown to
be a potent suppressor of oncogenesis in NOTCH1-induced
mouse T-cell acute lymphoblastic leukemia [36].
Thus, although considered of less significance, SS/LS
miRNAs were shown to have a significant role in a variety of
biological processes, while complementing the function of
conserved miRNAs.
Conserved miRNA expression variability
among different species holds functional
significance
As shown above, different miRNA repertoires in different
species can naturally shape developmental and physiological
changes during evolution. Different species can differ in their
genome collection of miRNAs or in sequence modification in a
given miRNA. Alternatively, an miRNA repertoire divergence
across different species, could be generated by varying the
temporal and spatial expression of the same miRNA
collection [75] (Fig. 1). It was shown that the timing and
location of conserved miRNA expression in fish, chickens, and
mice, e.g., is not strictly conserved [53, 76]. Such miRNA
expression variations were observed between distant species
(e.g. human and mouse [77]) as well as close ones (e.g. rhesus
and baboon [78] and different frog species [79]). Interestingly,
even SS miRNA expression can vary between its harboring
species. For example, the mouse- and rat-specific miRNAs,
miR-293, and miR-295, that might define mouse and
rat-specific traits [80], display a different spatial expression
pattern in these close species [81].
Intriguing evidence for the functional significance of
miRNA expression variability among different species was
provided for miR-320b, miR-454, and miR-92a. The expression
of these miRNAs in the prefrontal cortex was shown to vary
between humans and macaques or chimpanzees throughout
their lifespan [82]. The miRNA expression patterns could be
directly linked to alterations of their target genes expression
and thus can explain how hundreds of genes changed their
expression patterns in a coordinated manner during human
brain development. It was suggested that human cognitive
abilities might be traced to a handful of key miRNA expression
changes that remodeled cortical development [82].
While miRNA expression patterns can vary between
species under normal physiological conditions, it is likely
that some miRNA expression differences will only surface
upon exposure to stress or pathology [83]. Shah et al. [84] have
suggested that the susceptibility of rodents, but not humans,
5
 E. Mor and N. Shomron
to hepatocarcinogenicity following treatment with peroxi-
some proliferator chemicals, is associated with miRNA
regulation differences in rodents, but not humans, following
Review essays
exposure to these chemicals. miRNA expression differences
upon stress conditions (methyl-deficient diet) were also
apparent among hepatic miRNAs in different mice strains [85].
Thus, another means through which SS miRNA regulation
is achieved is by variable expression patterns of miRNAs in
different species.
Non-conserved miRNA binding sites add
another piece to the already complicated
paradigm of SS miRNA regulation
The relative contribution of conserved versus non-conserved
miRNA binding sites to the overall miRNA targeting is difficult
to define. Computational analyses have shown that only
10% of predicted target sites are conserved across species,
whereas the rest are not conserved [4, 53]. One study showed
that the false positive rate for predicted conserved miRNA
binding sites was estimated to be 22–31% [86], while 30–50%
of the non-conserved binding sites were estimated to be
functional when the mRNA and miRNA are endogenously
co-expressed [87]. Moreover, while extended seed match of
8-mer, more than that of a 7-mer, was shown to have a larger
effect on the mRNA target, non-conserved 8-mer seed matches
exhibit, on average, stronger repression than conserved 7-mer
seed matches [17].
The conserved let-7 miRNA family represents an example
of non-conserved miRNA targeting. While let-7 functions to
control differentiation and cell fate in different species, its
targets and the specific developmental pathways it regulates
differ in worms, flies, and humans [88–91]. In mammals, e.g.,
let-7 targets the oncogene HMGA2 [90, 92] while in worms or
flies, the HMGA2 orthologs are not targeted by let-7.
Another example is the role of the miR-430/427/302 family
in the regulation of vertebrate embryogenesis [38]. This
miRNA family displays SS target selection among ligands of
the Nodal pathway that plays a crucial role in germ layer
specification [38].
A recent study compared the 30 UTR sequences and the
miRNA binding sites of the progesterone receptor (PGR) in
different species [39]. This transcript is conserved among
primates, but poorly conserved between primates and
rodents. PGR was shown as directly targeted by miR-96 in
humans and rhesus monkeys but not in rodents, and by
miR-375 in rhesus monkey but not in humans or rodents [39].
While previous studies have indicated that long non-
coding RNAs (lncRNAs) can also be targeted by miRNAs
(e.g. [93]), the authors [39] also identified a primate-specific
lncRNA that is directly targeted by miR-219-5p, to further
regulate PGR expression. Thus, miRNA regulation of lncRNAs
represents an additional mechanism for SS miRNA regulation.
SS target recognition by miRNAs is further complicated in
the case of the non-conserved targeting of the TNF-a 30 -UTR by
the miR-125 family, including the mouse and rat-specific
miR-351 (Fig. 1, bottom right corner). The TNF-a binding site to
the miR-125 family, including miR-125b, is not conserved, as it
is present in mice but not in humans (Fig. 1, bottom right
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Prospects & Overviews ....
corner) (according to many target prediction software
(TargetScan [4], microRNA.org [94], miRDB [95], and others).
Yet, this binding site was considered functional in humans as
well based on its targeting extrapolation by miR-125 from mice
(e.g. [96]). Thus, this miRNA gene may contribute to mouse
and rat-specific traits compared to other species [29].
Interestingly, it may also contribute to the differences between
closely related species given that it targets TNF-a in mice but
not in rat astrocytes [29].
While the above examples demonstrate the implications of
low-conserved miRNA binding sites, other studies have failed
to acknowledge the low conservation of their preferred miRNA
binding site. Thus, regardless of the accurate proportion of
non-conserved, SS binding sites in the overall miRNA
targeting, it is clear that these binding sites add another piece
to the already complicated paradigm of SS miRNA regulation.
Conclusions
SS miRNA regulation is highly complex because it can be
viewed from different perspectives. First, many miRNAs are
non-conserved and can be found in some species but not in
others. Second, miRNAs tend to have variable expression
patterns in different species. And lastly, a large proportion of
the miRNA binding sites are non-conserved themselves.
Taking this into consideration, SS miRNA regulation and
targeting were shown to possess prominent functional
implications that underlie some of the well-known phenotypic
variability in different species. For example, the mouse- and
rat-specific miRNAs, miR-351 and miR-298, define different
responses to astrocyte activation in mice and rats, compared
to primates [29]. Another example comes from miR-320b,
miR-454, and miR-92a. While these miRNAs differ in their
expression patterns in human brain development compared to
other primates, they can be attributed to improved human
cognitive abilities [82].
We thus argue that paying attention to SS miRNAs is of
importance and implications of regulation by SS miRNAs are
sure to strengthen in the coming years.
Acknowledgments
We would like to acknowledge Corinne Carland for going over
this manuscript and Orna Ernst for providing the activated
peritoneal macrophages and RAW264.7 cells. The Shomron
laboratory is supported by the National Institutes of Health
(NIDCD) R01DC011835; Israel Cancer Association; Wolfson
Family Charitable Fund; Claire and Amedee Maratier Institute
for the Study of Blindness and Visual Disorders; I-CORE
Program of the Planning and Budgeting Committee, The Israel
Science Foundation (grant number 41/11).
The authors have declared no conflict of interest
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