Chromosome Organization within the Nucleus
9
genes whose transcripts are nonrandomly
localized relative to the nucleus: if the
corresponding gene was nonrandomly lo-
ca
l
izedtotheNEnea
rthes
i
teo
ffu
tu
re
message accumulation, then locally in-
creased export through the nearby nuclear
pores could explain the ultimate asymmet-
ric transcript localization. The fact that
some transcript localization is perturbed
in a nuclear lamin mutant might tend to
support this model.
Although these studies raised the possi-
bility that active genes might be targeted
to the NE, in most cases it has been
found that active genes are, in fact, non-
randomly localized to the nuclear interior
and not to the NE. As for a role of the NE
in transcript localization, a careful study
of many pair-rule genes in
Drosophila
,
whose transcripts are speciFcally localized
relative to the nucleus, revealed no re-
lation between the position of the gene
in the nucleus and the position of tran-
script accumulation. These studies suggest
that gene gating probably does not play
any signiFcant role in transcript targeting
or export.
5.3
Nuclear Compartmentalization and Gene
Expression
Heterochromatin tends
to
be
nonuni-
formly
distributed
in
cells.
In
most
cell types, the heterochromatin aggre-
gates
into
a
small
number
of
large
domains, and when euchromatic genes
become silenced by heterochromatic in-
sertions (a phenomenon called
position
effect variegation
in
Drosophila
), the genes
become localized to
these large
hete-
rochromatin domains. This relocalization
probably plays a causal role: when a eu-
chromatic reporter gene was artiFcially
targeted to the heterochromatin domain
in
Drosophila
by flanking chromosome
pairing sites, the gene became silenced.
Moreover, chromosome rearrangements
that impede localization of a gene to
the heterochromatin domain have the
effect
of
reducing
silencing.
Thus,
a
probable model is that the heterochro-
matin domain creates a ‘‘bad neighbor-
hood’’ for transcription of euchromatic
genes, and that when genes are brought
into this neighborhood they tend to be-
come silenced.
This model may also explain the ability
of certain sequences (known as
insulators
)
to protect nearby euchromatic genes from
silencing by heterochromatin. The gypsy
insulator protects genes from silencing
by nearby heterochromatin, and its func-
tion requires the Su(hw) and mod(mdg4)
proteins. These two proteins localize to
the NE, as does the gypsy insulator it-
self. Su(hw) mutants that prevent insulator
function cause the insulator sequence to
dissociate from the NE. These results im-
ply that Su(hw) protein tethers insulator
sequences to the NE, and more impor-
tantly, that possibly this tethering could
be critical in insulator function. One way
this would work would be to lock genes
in place near the NE, preventing them
from relocating from their initial position
into the silenced heterochromatin com-
partment.
6
Role of Nuclear Architecture in
Chromosome Interactions
6.1
Regulation of Interactions by Constrained
Diffusion
Many aspects of DNA metabolism involve
interactions between widely separated loci.
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