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between temporal collinearity and the presence of an uninterrupted
Hox
gene cluster (
Duboule, 1994
). In Amphioxus, indeed, the time-sequence
in
Hox
genes activation occurs on the top of a relatively well organized
Hox
gene cluster (
Fig. 4.3
;
Holland, Albalat, et al., 2008; Holland,
Holland, et al., 2008b
). In this view, the sequential transition of every gene
from one domain to the other would act as a timer (the
Hox
clock). How-
ever, the underlying mechanism(s) that is the driving force responsible for
this unidirectional transcriptional activation remains elusive.
Temporal collinearity correlates with the step-wise removal of H3K27me3
marks, from one extremity of the cluster to the other, at the same time H3K4
becomes trimethylated. As a result, local enhancersmay be progressivelymobi-
lized, making
Hox
genes available for transcription (
Noordermeer et al., 2011;
Tschopp et al., 2009
). The directionality of this mechanism may rely on an
intrinsic polarity of
Hox
clusters, either for repressive or for activating (or both)
protein complexes. Polarized effects have been reported when the overall
amount of PRC1 components was decreased, via the deletion either of
CBX2 (one of the four mammalian PC orthologous genes) or of BMI1
(one of two mammalian PSC orthologous genes). In both cases,
Hox
gene
activity was anteriorized (
Bel-Vialar et al., 2000; van der Lugt, Alkema,
Berns, & Deschamps, 1996
), whereas the opposite effect was scored in mice
overexpressing PRC1 components (
Alkema, van der Lugt, Bobeldijk,
Berns, & van Lohuizen, 1995; van der Lugt et al., 1996
). In both cases though,
collinearity was maintained.
8. A REGULATORY ARCHIPELAGO AND COLLINEARITY
IN DEVELOPING DIGITS
During the development of tetrapod digits, the five genes located at
the posterior extremity of the
HoxD
cluster (
Hoxd9
to
Hoxd13
) are
transcribed with an intensity decreasing along with their relative genomic
position, with a maximal expression for
Hoxd13
(
Fig. 4.4
C;
Dolle,
Izpisua-Belmonte, Falkenstein, Renucci, & Duboule, 1989; Montavon
et al., 2008
). By using a targeted enhancer trap system, two regulatory
regions, Prox and GCR, located centromeric to the gene cluster, were iden-
tified as digit enhancers (
Fig. 4.8
A;
Gonzalez, Duboule, & Spitz, 2007; Spitz,
Gonzalez, & Duboule, 2003
). Subsequently, 4C experiments using
Hoxd13
as a viewpoint identified five additional islands of high interaction, all located
in the centromeric gene desert (
Fig. 4.8
A;
Montavon et al., 2011
). Scanning
deletion studies carried out
in embryo
, as well as transgenic reporter assays
