Biology Reference
In-Depth Information
A
HoxD
cluster + surroundings
(
Mus musculus
)
I
II
III
IV
V
GCR
Prox
100 kb
B
HoxD cluster
Mouse E12.5 digits
(
Mus musculus
)
HoxD cluster
Other genes
Regulatory regions
I
IV
GCR
II
II
I
Prox
Developing digit cells
(expressing)
Brain cells
(non expressing)
Figure 4.8 3D organization of the mouse HoxD cluster during quantitative collinearity
in embryonic digits. (A) Genomic organization of the mouse HoxD cluster and surround-
ing gene deserts. The HoxD cluster is indicated in black and other genes in grey. Reg-
ulatory regions involved in developing digits are indicated by black stars. (B) Schematic
2D representation of long-range chromatin interactions at the HoxD cluster in develop-
ing digits (left) and nonexpressing brain cells (right), as determined by Chromosome
Conformation Capture-on-Chip. Panel (B) based on data from
Montavon et al. (2011)
.
confirmed the functional importance of at least five of these elements for
Hox
gene in the developing digits.
Targeted deletions of increasing numbers of regulatory elements within
this “regulatory archipelago” had additive effects on
Hoxd
gene activity
(
Fig. 4.8
B;
Montavon et al., 2011
), whereas various deletions within the
5
0
-located target
Hoxd
genes resulted in regulatory reallocations, leading
to the upregulation of the remaining genes (
Montavon et al., 2008
). Also,
the integration of a supernumerary copy of
Hoxd9
into the centromeric gene
desert led to a decreased transcription of the native target genes, via a titra-
tion effect (
Monge, Kondo, & Duboule, 2003
).
Whether these complex and multiple enhancer-promoter interactions
are somehow determined, for example by forming a large and rather static
structure, or are stochastic and dynamic with various interactions occurring
at different times and frequencies, is difficult to evaluate with the currently
available technology. It is clear, however, that such distal enhancers can spe-
cifically activate the 5
0
-located
Hoxd
genes, while 3
0
-located genes are con-
comitantly repressed. As such, these interactions override the regulatory
polarity of the
HoxD
cluster as observed along the embryonic AP axis
(see above).
This situation illustrates how a novel collinear transcriptional program
can be co-opted by using the preexisting functional organization of
Hox
