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clusters. In this particular case, the evolution of strong enhancer sequences
outside the gene cluster induced an “opposite” directionality in the collinear
mechanism, thus overriding the polarity as observed along the AP axis. Anal-
ogous to the situation in the embryonic AP axis, genes heavily transcribed in
developing digits form a discrete 3D compartment, as detected by 4C ana-
lyses (
Montavon et al., 2011; Noordermeer et al., 2011
). This compartmen-
talization may help active genes to engage for interactions with distant
regulatory elements in the nuclear space, in addition to increasing the local
concentration of activating factors.
In embryonic brain cells,
Hoxd13
also contacted several regulatory islands
even though all
Hox
genes are fully inactive (
Fig. 4.8
B, right;
Montavon et al.,
2011
). These interactions may be part of a constitutive “prestructure”
(groundstate) that provides scaffolding for efficient formation of long-range
interactions in developing digits. Conversely, the inactive
Hoxd4
gene, in brain
cells, established contacts with the telomeric neighborhood of the
HoxD
cluster. This polarity in the contacts is similar towhat was observed in the ante-
rior part of the trunk, where
Hoxd13
is inactive, whereas
Hoxd4
is active
(
Noordermeer et al., 2011
). In the case of the developing limbs, this structural
polarity observed at the
HoxD
cluster matches a partitioning of the regulatory
landscapes. The early collinear activation of
Hoxd
genes in the future proximal
part of the limb relies on regulatory elements located telomeric to the cluster,
whereas subsequent transcriptional control, during digit development origi-
nates from the centromeric gene desert (
Spitz et al., 2005
).
Therefore, while inactive
Hox
clusters appear as single, largely homoge-
neous and local 3D compartments (see above), a directionality exists in long-
range contacts, outside the cluster itself, regardless whether active or inactive
cells are considered. Such genomic domains of constitutive long-range
interactions (topological domains) are a common feature of the mouse
and human ES cell genome (
Dixon et al., 2012; Nora et al., 2012
) and have
been proposed to form “enhancer-promoter units,” in which genes and
their cell type-specific enhancers are contained (
Nora et al., 2012; Shen
et al., 2012
). Besides facilitating the formation of long-range interactions
between regulatory elements and target genes, these domains may also
reduce interactions with nontarget genes, located outside the domain. A fur-
ther reinforcement of regulatory maintenance may thus be achieved by
long-range compartmentalization. In this context, it is noteworthy that
the interaction domain observed between
Hoxd13
and its centromeric reg-
ulatory archipelago matches one such topological domain as reported by
Ren and colleagues in ES cells (
Dixon et al., 2012
).
