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member of the
miR-133
family (
Chen
et al
., 2006
;
Liu
et al
., 2007
;
Rao
et al
.,
2006
). Such bicistronic organization places distinct miRNAs under common
transcriptional control. Indeed, one member of the
miR-1
family,
mir-206
,
and its neighbor,
miR-133b
, are specifically expressed in mouse skeletal
muscle but not in the heart (
McCarthy, 2008
). The other two
miR-1
/
miR-
133
clusters, located on mouse chromosomes 2 and 18, are transcriptionally
activated in skeletal as well as cardiac muscle (
Liu
et al
., 2007
;
Zhao
et al
.,
2005
). Since
miR-1
miRNAs are
10-fold more abundant in heart tissue
than
miR-133
miRNAs, these cotranscribedmiRNAs are likely the targets of
differential posttranscriptional control (
Rao
et al
., 2009
). The functional
significance of the differential expression of
miR-1
and
miR-133
is currently
unknown, however. The bicistronic genomic organization of vertebrate
miR-1
/
miR-206
and
miR-133
is reflected in the
D. melanogaster
genome as
well, where the single copy of
miR-1
is located
130kb away from
miR-133
,
relatively close in genomic terms. Although RNA profiling indicates that fly
miR-1
and
miR-133
have distinct temporal expression profiles and are not
cotranscribed (
Graveley
et al
., 2011
), the spatial expression pattern of
miR-
133
has not been reported, so it may be expressed in muscles and under the
control of enhancers it shares with
miR-1
. Other vertebrate muscle miRNAs
also display bicistronic organization, including the unrelated smooth muscle
miRNAs
miR-143
and
miR-145
(
Cordes
et al
., 2009
).
Muscle miRNAs can also be found within the introns of myogenic loci
(see
Fig. 3.1
). For example,
miR-208a
,
miR-208b,
and
miR-499
are located
in the introns of three corresponding myosin genes:
myh6
,
myh7
, and
myh7b,
respectively (
Callis
et al
., 2009
;
van Rooij
et al
., 2007, 2009
). This
genomic organization is intriguing, particularly because the
myh6
and
myh7
loci encode proteins that display nonoverlapping expression profiles that are
shared by their intronic miRNAs.
myh6
and
myh7
encode
a
-cardiac muscle
myosin heavy chain (
a
-MHC) and
b
-cardiac muscle myosin heavy chain
(
b
-MHC), respectively. The ratio of
a
-MHC and
b
-MHC is under tight
transcriptional control since it controls cardiac contractility:
b
-MHC is
expressed during embryonic development and is downregulated shortly
after birth when
a
-MHC is upregulated. The intronic miRNAs display
these same patterns of temporal expression, with
miR-208a
abundantly
expressed in fetal but not in adult hearts and
miR-208b
expressed in the
opposite pattern (
Callis
et al
., 2009
). This is due to the transcription of the
intronic miRNAs from their host genes, although
miR-208b
can also be
independently controlled by an intronic promoter (
Monteys
et al
., 2010
).
Knockout analysis of the miRNAs, described below, indicates that these
miRNAs are not required to ensure the mutually exclusive expression
profiles of
a
-MHC and
b
-MHC. Nevertheless, the structural relationship
between
miR-208
and myosin family members is conserved from fish to
humans, indicating that the coexpression of the intronic miRNAs with
their myosin host genes is important for muscle function.