Biology Reference
In-Depth Information
transcriptional and posttranscriptional regulatory mechanisms that operate
in this system will be an important area for future study.
Another important question raised by these experiments is why Ubx
levels are affected only at late gastrula stages, despite the earlier and compel-
lingly complementary expression with both miRNAs. In fact,
Ubx
has
alternate polyadenylation sites that produce transcripts with varied degrees
of miRNA regulation. The shorter transcript predominates at early stages
and loss of
miR-iab4/8
has no effect on its expression levels despite bearing
three predicted binding sites. The inclusion of distal 3
0
UTR sequence,
which incorporates an additional four potential
miR-iab-4/8
binding sites
and is expressed at later stages, confers miRNA regulation (
Bender, 2008
;
Thomsen
et al
., 2010
). This principle was further extended to other Hox
genes
abd-A
,
Abd-B
, and
Antp
, all of which exhibit the same striking use of
alternate polyadenylation resulting in either masking or availability of these
transcripts to miRNA control. It is possible that early
miR-iab-4/8
expres-
sion is not functional and could even be due simply to coregulation with
Abd-A and Abd-B, respectively. Alternatively, it may be that these miR-
NAs can repress the shorter transcript variants, though to a lesser extent,
while serving in a failsafe mode; for example, they could prevent Ubx
expression that is also repressed by Abd-A and Abd-B. Such a role could
be tested by generating compound mutant animals. Further, how these Hox
transcripts collectively switch to the long, miRNA-regulated form at a
particular stage of development is an important question for future investi-
gation. Whether similar mechanisms exist in mammalian Hox gene regula-
tion is unknown; however, both mouse
Hoxa-4
and
Hoxa-7
transcripts have
alternative polyadenylation sites which have the potential to alter the
amplitude of Hox-embedded miRNA regulation (
Yekta
et al
., 2008
). The
temporal and spatial division of alternate transcript expression and their
in vivo
relevance is yet to be determined.
6.
miR-196
6.1. Transcript structure, processing, and upstream
regulatory mechanisms
miR-196
regulatory elements have not been characterized, but there
is evidence that many
miR-196
paralogs are cotranscribed with protein-
coding Hox genes. Polycistronic transcripts containing
miR-196
pre-miR-
NAs within introns have been cloned for
Hoxa-5
(
X. tropicalis
),
Hoxa-9
(human, mouse, guinea pig, and zebrafish),
HoxB-7
(human),
Hoxb-9
(
X.
tropicalis
),
HoxC-5
(human),
HoxC-6
(human),
Hoxc-9
(
X. tropicalis
), and
Hox
C
10a
(zebrafish) (
Benson
et al
., 2004
;
Griffiths-Jones, 2004
;
Mainguy
et al
., 2007
;
Tang and Maxwell, 2008
). In addition, an antisense transcript
