Biology Reference
In-Depth Information
2.3. Transcriptional control of muscle miRNAs
Muscle miRNAs are well integrated within myogenic transcriptional regu-
latory networks. Intronic miRNAs like
miR-208a
,
miR-208b,
and
miR-
499
, for example, are under the same transcriptional control as their myosin
hosts. Intergenic miRNAs are also targeted by myogenic transcription
factors. For example, transcription of
miR-1
and
miR-133
in skeletal muscle
is controlled by the myogenic transcription factor MyoD, while their
transcription in cardiac muscle is controlled by cardiogenic transcription
factors SRF and MEF2 (
Liu
et al
., 2007
;
Zhao
et al
., 2005
). The transcrip-
tional regulation of
miR-1
by MEF2 is highly conserved, since MEF2
coregulates
miR-1
expression in flies along with the mesodermal transcrip-
tion factor Twist (
Biemar
et al
., 2005
;
Kwon
et al
., 2005
;
Sokol and Ambros,
2005
). In addition to the
miR-1
/
miR-133
cluster, vertebrate SRF activates
the smooth muscle miRNA
miR-143
/
miR-145
cluster together with its
coactivator myocardin (
Cordes
et al
., 2009
;
Xin
et al
., 2009
). Predicted SRF
binding sites are located near another 40 miRNA loci (
Niu
et al
., 2007
), so it
will be interesting to see how many of these are directly controlled by SRF.
2.4. Posttranscriptional regulation of muscle miRNAs
miRNA expression is also regulated at the posttranscriptional level. miR-
NAs are transcribed within long primary transcripts, which are cleaved
twice to release functional 21-nt RNAs. The Dicer and Drosha enzymes
carry out these sequential cleavages, and their activities can be modulated by
an emerging repertoire of auxiliary RNA-binding proteins including
KSRP, p68, and Lin-28 (
Davis
et al
., 2008
;
Suzuki
et al
., 2009
;
Trabucchi
et al
., 2009
;
Viswanathan
et al
., 2008
). KSRP is a KH-type splicing regu-
latory protein that physically associates with both Dicer and Drosha to
promote the biogenesis of a subset of miRNAs, including
miR-1
and
miR-206
during skeletal muscle differentiation of murine C2C12 cells
(
Trabucchi
et al
., 2009
). Similarly, the DEAD-box RNA helicase p68
interacts with the Drosha processing complex to enhance the posttranscrip-
tional processing of the smooth muscle miRNAs
miR-21
,
miR-143,
and
miR-145
(
Davis
et al
., 2008
;
Suzuki
et al
., 2009
). p68 is a key regulatory
component of the Drosha complex, since it is targeted by the TGF-B
pathway to promote
miR-21
processing (
Davis
et al
., 2008
) and by the
p53 tumor suppressor protein to promote
miR-143
and
miR-145
processing
(
Suzuki
et al
., 2009
). Unlike KSRP and p68, the pluripotency factor Lin-28
is a negative regulator of miRNA biogenesis and targets
let-7
(
Viswanathan
and Daley, 2010
;
Viswanathan
et al
., 2008
). Recently,
pre-miR-1
was also
identified as a target of Lin-28 (
Rau
et al
., 2011
), which is strongly induced
during the differentiation of adult primary myoblasts (
Polesskaya
et al
., 2007
;
Viswanathan
et al
., 2008
). Collectively, the studies summarized here identify
