Biology Reference
In-Depth Information
4.
miR-10
4.1. Transcript structure, processing, and
regulatory mechanisms
Little is known about the structure of
miR-10
regulatory elements. A
miR-
10a
proximal enhancer active during smooth muscle differentiation has
been defined in mouse, but it is not clear whether it functions in other
contexts (
Huang
et al
., 2010a
). Interestingly,
miR-10
is frequently cotran-
scribed with
Hox3
or
Hox4
genes in vertebrates. In zebrafish, a polycistronic
transcript originating near the
HoxB5a
transcription start site contains the
HoxB3a
coding sequence and
miR-10c
within an intron (
Hadrys
et al
., 2004
;
Woltering and Durston, 2008
). Consistent with colinearity, this transcript
has an anterior boundary of expression similar to
HoxB5a
though it is not
translated since its expression does not overlap with HoxB3 protein. Inter-
estingly, the transcript is upregulated following
miR-10
knockdown sug-
gesting autoregulation by
miR-10
(
Woltering and Durston, 2008
). EST
libraries further reveal cotranscription of human
HoxB-3
with
miR-10a
and
HoxD-3
with
miR-10b,
and mouse
miR-10b
with
Hoxd-3
or
Hoxd-4
(
Benson
et al
., 2004
;
Mainguy
et al
., 2007
). It has been proposed that via
polycistronic transcription,
miR-10
(and perhaps other Hox-embedded
miRNAs) may be important to block expression of aberrant Hox transcripts
that arise due to the proximity of regulatory elements within Hox clusters
(
Woltering and Durston, 2008
). Defining the number and usage of
miR-10
promoters and enhancers, and testing the functional significance of polycis-
tronic transcripts, will be an important area of future study.
In
C. elegans,
the
miR-10-
related gene
miR-57
is not clustered with Hox
genes. A
miR-57
enhancer that recapitulates its expression pattern was
defined using reporter assays, and it is regulated by the Abd homolog
Nob
-
1(
Zhao
et al
., 2010
; discussed further in
Section 4.2.2
).
miR-10
transcript structure and regulation in other invertebrates is not well char-
acterized. In
Drosophila
,
miR-10
is alternatively spliced and, although the
significance of this is unknown, both isoforms include the mature miRNA
(
Qian
et al
., 2011
).
In addition to variable transcript structures,
miR-10
is subject to exten-
sive posttranscriptional processing. Despite the unusually high conservation
of this gene (
Ruby
et al
., 2007
;
Wheeler
et al
., 2009
), a diversity of mature
transcripts are produced, suggesting functional specialization within and
across species. First, transcripts processed from both arms of the pre-
miRNA (which have different target specificities) have been cloned from
many organisms (
Landgraf
et al
., 2007
;
Lim
et al
., 2003
;
Ruby
et al
., 2007
;
Stark
et al
., 2007
;
Wheeler
et al
., 2009
). Further, the expression ratio of the
5p and 3p products varies across species, a phenomenon termed arm
