8
Chromosome Organization within the Nucleus
4.3
Evidence for Active Chromatin Movement
In addition to this constrained diffusion,
it also appears that loci can undergo active
directed movements, at least in some
cases. When centromeres in animal cells
were tracked
in vivo
,i
tw
a
sf
oundth
a
t
the centromeres occasionally experienced
persistent
directed
movements
in
the
interphase nucleus. Another study showed
large
directed shifts
in
gene
position
during
the
mid-blastula
transition
in
Drosophila
embryos, possibly driven by the
force of heterochromatin condensation.
5
Regulation of Gene Expression by Nuclear
Architecture
5.1
Role of Nuclear Envelope Interactions in
Gene Silencing
Heterochromatin, the highly condensed
transcriptionally silenced regions of the
genome, is generally seen near the NE
in electron microscopy studies. Indeed,
insertion of a block of heterochromatin
into a euchromatic position is sufFcient
to locate the whole region onto the NE.
More speciFc ±ISH studies of individual
chromosomes have found that gene-poor
chromosomes with reduced overall tran-
scription tend to be NE associated. These
results raise the possibility that the NE
might play some role in establishment of
silenced heterochromatin. Indeed, target-
ing a reporter gene to the NE by means
of an NE-interacting DNA-binding fu-
sion protein results in silencing of the
gene, and induced transcriptional acti-
vation of a reporter locus caused the
locus to dissociate from the NE
and
move to the nuclear interior. Mutations
in the telomere-binding protein dimer
yKu70/yKu80 and the NPC associated
proteins Mlp1/Mlp2 cause telomeres to
dissociate from the NE and result in loss
of telomeric silencing, again suggesting
that NE interactions play some role in
gene silencing. The SIR3 and SIR4 silenc-
ing proteins in yeast are associated with
the NE, which suggests a simple model
that genes associated with the NE ex-
perience a higher local concentration of
silencing proteins.
Another potential example of the NE
playing a role in gene repression comes
from studies of the lamin-associated pro-
tein 2 beta (LAP2
β
), an integral membrane
protein component of the nuclear lamina.
Ectopic expression of LAP2
β
and its bind-
ing partner GCL (germ cell-less) in cells
that do not normally express GCL, reduces
transcriptional induction by the E2±-DP
complex, which binds GCL. This raises the
possibility that Lap2
β
and GCL could re-
cruit E2±-regulated genes to the NE where
they would become silenced.
5.2
Gene Gating
Although most studies suggest that the
NE exerts a negative effect on gene ex-
pression, a possible positive correlation
between gene expression and NE localiza-
tion was suggested by the increased nucle-
ase sensitivity of NE-associated chromatin.
Since increased nuclease accessibility usu-
ally correlates with gene expression, these
studies suggested that NE-associated chro-
matin might be enriched for active genes.
Since mRNA must be exported through
NPCs, it was proposed that perhaps active
genes were targeted to the NE in order
to facilitate transcript export, a hypoth-
esis known as
gene gating
.G
en
eg
a
t
in
g
is particularly appealing in the case of
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