Nuclear Envelope Disease and Chromatin Organization
Chromobility: the rapid movement of
chromosomes in interphase nuclei
Joanna M. Bridger1
Laboratory of Nuclear and Genomic Health, Centre of Cell and Chromosome Biology, Biosciences, School of Health Sciences and Social Care, Brunel
University, Uxbridge, London UB8 3PH, U.K.
Abstract
There are an increasing number of studies reporting the movement of gene loci and whole chromosomes to
new compartments within interphase nuclei. Some of the movements can be rapid, with relocation of parts
of the genome within less than 15 min over a number of microns. Some of these studies have also revealed
that the activity of motor proteins such as actin and myosin are responsible for these long-range movements
of chromatin. Within the nuclear biology field, there remains some controversy over the presence of an active
nuclear acto–myosin motor in interphase nuclei. However, both actin and myosin isoforms are localized to
the nucleus, and there is a requirement for rapid and directed movements of genes and whole chromosomes
and evidence for the involvement of motor proteins in this relocation. The presence of nuclear motors for
chromatin movement is thus an important and timely debate to have.
Introduction
It is now well accepted that the genomes of eukaryotic
cells are highly spatially organized in interphase nuclei
as individual chromosome territories. These territories
exhibit non-random radial positioning [1]. The non-random
nuclear location and positioning of individual chromosome
territories can be differential in cells from different origins,
before and after differentiation pathway steps, or in disease
[2]. This implies that, whatever state cells are in, chromosomes
have preferred and regulated locations within nuclei.
However, randomness of chromosome territory positioning
can be seen as cells are reorganizing or rebuilding their nuclei,
for example, at the very beginning of G1 -phase [3–5].
With respect to gene movement, there are now numerous
examples of where small regions of chromosomes loop away
from the main body of a chromosome territory [2]. Further
studies have revealed where these genes are headed, revealing
an association with a facilitating nuclear structure, such as
various nuclear bodies and transcription factories [6–9].
The relocation of individual genes to nuclear structures
that may aid their expression is perhaps easier to comprehend
than why whole chromosome territories would relocate.
After mitosis, a chromosome would have the opportunity
to change its nuclear location, presumably by having its
chromatin modified and/or being able to interact with
different nuclear structures. This situation would not require
an active mechanism within nuclei to move chromosomes
around. However, specific chromosomes can change their
nuclear location after stimuli, moving from one nuclear
location to another without rebuilding a new nucleus after
Key words: chromobility, chromosome territory, gene repositioning, nuclear actin, nuclear body,
nuclear motor, nuclear myosin 1β.
Abbreviations used: F-actin, filamentous actin; GFP, green fluorescent protein; HDF, human
dermal fibroblast; NM1β, nuclear myosin 1β; snRNA, small nuclear RNA.
email [email protected]
1
Biochem. Soc. Trans. (2011) 39, 1747–1751; doi:10.1042/BST20110696
mitosis. We have demonstrated this in proliferating human
dermal fibroblasts that have been placed in low serum [10].
This situation would require a mechanism presumably within
nuclei that elicits this movement, although there could be
connections with the cytoplasm. Studying a system such as
this will allow us to ask where the chromosomes are being
directed, which nuclear compartments and/or structures
are functionally important, what are the consequences of
repositioning chromosomes with respect to gene expression
and silencing and what can happen to a cell/organism when
this repositioning is faulty. My group are now trying to
answer these questions using assay systems where genes and
chromosomes do change position rapidly after stimuli such
as removal of growth factors [10], addition of differentiation
factors [11] and parasite exposure [12]. One of the keys
to understanding what is happening to chromosomes and
genes is the rate at which this repositioning can occur.
Whole chromosomes and gene loci on loops have been
observed changing nuclear location as rapidly as 1 μm/min
with neighbouring chromosomal regions and chromosomes
remaining stationary. It most certainly involves chromatin
modification, but how does this alone allow a change in
position, sometimes of over 10 μm?
The nucleus is full of structural proteins that could create
a dynamic scaffolding network that chromatin could bind
to and be released from through signalling and protein
modification. This could mean that, if chromatin were
released from one region of the nucleus, it could be random
or corralled diffusion that influences where the chromatin
ends up being located and/or re-anchoring. The data from
some studies do not necessarily support this serendipitous
route of relocation, but favour active and directed movement
to new non-random locations or specific structures within
the nucleus. If a gene needs to be located at a specific nuclear
structure such as a nuclear body, a speckle or transcription
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factory, then it may be that the gene is relocated to the nearest
one. However, since co-transcribed regions of the genome
are from different chromosome territories and are found colocalized at the same nuclear entity [7,9,13,14], this implies
that there is co-ordinated movement of genes from different
chromosomes to co-occupy nuclear bodies or factories.
So the hypothesis examined in the present paper is that
whole chromosomes and subchromosomal regions can be
relocated rapidly and directed to specific nuclear locations.
We believe that these regions of chromatin are moved around
the nucleus on a network of molecular motors, similar
to those found in the cytoplasm. Indeed, the components
of such a transport system could include nuclear actin
and nuclear myosins working together in concert to move
DNA/chromatin cargo around the nucleus.
Nuclear presence of actin and myosin
Both actin and myosin have been located in the nucleus
from early on in the study of nuclear biology, but the
belief in the presence of either molecule was blighted by
accusations of cytoplasmic contamination. However, with
more sophisticated methodologies and technologies, the
acceptance of both of these proteins in the nucleus is gaining
credence.
The first papers to discuss the presence of nucleoplasmic
actin showed the actin in networks in Xenopus oocytes (see
[15]). Other reports followed describing actin in the nuclei
of cells from a range of different species, such as bovine
lymphocytes and slime mould (see [15]). With respect to
the different forms of actin, G-actin (globular actin) and Factin (filamentous actin) have been revealed in the nucleus
using anti-actin antibodies [16,17], as well as in FRAP
(fluorescence recovery after photobleaching) studies using
GFP (green fluorescent protein)–actin [18]. β-Actin was
shown to bind the chromatin-modelling protein BAF (barrier
to autointegration factor) in vivo [19]. However, there may
be less conventional forms of actin in the nucleus that are not
polymeric in form and are revealed with specially designed
antibodies. These antibodies reveal accumulations of actin
and a concentration of actin throughout the nucleoplasm [20].
With respect to the movement of chromatin, perhaps the most
important study so far revealing nuclear actin employment
in chromatin movement is that a β-actin dominant-negative
mutant expressed in HeLa cells blocked the movement of
gene loci to Cajal bodies [6].
Myosin isoforms were originally found in the nucleus
of Acanthamoeba cells when an antibody against myosin I
revealed myosin in the nucleoplasm [21]. Furthermore,
myosin II heavy-chain-like protein was found proximal to
nuclear pore complexes in Drosophila [22]. More recently,
different myosin isoforms have been located in nuclei. These
are NM1β (nuclear myosin 1β) [23,24], myosin VI [25],
myosin 16b [26], myosin Va [27] and myosin Vb [28].
Myosin VI has been found to have a role in the DNA-damage
response [29], and myosin 16b appears to be involved in DNA
replication [26]. So far, NM1β has been the myosin candidate
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nucleus [10,15].
NM1β has a single globular head and a single heavy chain
structure [15]. NM1β also contains a unique 16-residue
amino acid extension at its N-terminus which is required for
nuclear import [24]. The nuclear distribution of NM1β is
throughout the nucleoplasm with a concentration at nucleoli
[10,23,24,30,31]. In addition, NM1β has also been found
localized at the nuclear envelope in proliferating HDFs
(human dermal fibroblasts) [10,15]. In non-proliferating
HDFs, NM1β is reorganized into large aggregates deep
within the nucleoplasm ([10,15], and I.S. Mehta, K.J.
Meaburn, M. Figgitt, I.R. Kill and J.M. Bridger, unpublished
work). Interestingly, these large aggregates are found in
proliferating HDFs from Hutchinson–Gilford progeria
syndrome patients, but a normal distribution of NM1β is
restored after treatment with drugs that ameliorate some of
the abnormalities in these cells [32].
Repositioning of gene loci and whole
chromosomes
Individual chromosomes and gene loci have been shown
to change their nuclear location upon stimuli, whether that
be stimuli to induce differentiation [11,33–36], signals that
change growth status [10,37,38], environmental stimuli [12]
or compounds to induce exogenous gene expression [39]. The
consensus hypothesis in the field is that whole chromosomes
are moved to allow some control over genes that are
housed upon that chromosome, whether for expression
or for repression. Gene loci may be relocated to a new
region of the nucleus with the movement of the whole
chromosome territory, but genes can also be repositioned by
chromatin looping outside the main body of the chromosome
territory. Chromatin looped out of territories has been
shown to become associated with nuclear structures such as
Cajal bodies [6], splicing speckles/SC35 domains [7,14] and
transcription factories [9]. Individual genes and genes from
different chromosomes that are co-regulated can be found at
the same transcription factories [9].
Evidence for directed chromosome and
gene relocation elicited through nuclear
motor activity
The hypothesis that a nuclear motor mechanism is required
to relocate a gene/genomic regions or whole chromosome
has been tested in a few studies. The involvement of actin
and/or myosin in the directed movement of a chromosome
or a region of a chromosome can be assayed by employing
drugs that interfere with the polymerization and the activity
of actin and myosins, by introducing mutant nuclear motor
proteins into cells, or using RNA interference technology
to knock down specific nuclear motor proteins. Indeed,
Belmont and colleagues used both drugs to treat cells and
transfected with mutant actin, to test whether an activated
exogenous lac operator integrated array, tagged by bound
Nuclear Envelope Disease and Chromatin Organization
GFP–lac repressor protein, was relocated and whether this
was due to motor activity [39]. These experiments were
performed in live cells using time-lapse microscopy and
showed that the activated gene moved from the nuclear
periphery towards the nuclear interior, whether or not
transcription was activated. The loci on average moved 3 μm
in 2 h, but there were short bursts of rapid directed
movement of 1 μm/min. Furthermore, transfection of an
actin mutant lacking the ability to polymerize also blocked
the repositioning. However, when the authors used an actin
mutant that permitted F-actin to polymerize, the array was
still able to move, implying that it is the polymeric F-actin
that is required to move chromatin [39].
A further study by the Matera group has shown that tagged
U2 snRNA (small nuclear RNA) repeats containing the
lac operator arrays collide with GFP-labelled Cajal bodies.
Using sophisticated imaging and analysis, it appeared that
there was a final directed collision of array and body, which
resulted in association. The U2 snRNA array was often
found on a loop emanating away from the main chromosome
territory directed towards the Cajal body. This movement of
the chromatin loop was inhibited when a polymerizationdeficient actin mutant was expressed in the cells. In this
situation, neither chromatin looping of the U2 array was seen
nor array–Cajal body association [6].
We were one of the first groups to show that whole
chromosome movement in interphase nuclei relies on the
activity of actin and nuclear myosin. We have shown that,
although chromosomes are positioned non-randomly in
nuclei, some of them change nuclear location when cells
become arrested either irreversibly in replicative senescence
or reversibly in quiescence [10,40,41]. Indeed, when serum
is removed from proliferating cultures, chromosomes move
towards the nuclear periphery, whereas some move away to
the nuclear interior and some chromosomes do not move
at all. These findings suggested that there must be specific
individual targeted chromosome movement occurring. One
of the most interesting chromosomes was chromosome
10. It was found at the nuclear periphery in quiescent
HDFs, at an intermediate position in proliferating HDFs
and in the nuclear interior in senescent HDFs ([10,41], and
I.S. Mehta, K.J. Meaburn, M. Figgitt, I.R. Kill and J.M.
Bridger, unpublished work). In order to determine the rate
of chromosome relocation, proliferating cells were placed
in low serum and chromosome positioning was analysed to
reveal when the relocation of chromosomes took place, i.e.
from 0 min to 7 days. Chromosomes did not take days to
relocate, but moved within 15 min of the high serum being
removed. This indicated that the movement was active and
directed, so, given recent evidence of actin and myosin in
the nucleus, it was pertinent to determine whether these
nuclear motor proteins were involved. This was achieved by
using drugs to inhibit actin and/or myosin polymerization
and activity. Three drugs did prevent the chromosomal
movement: butane-2,3-dionemonoxime, latrunculin A and
jasplakinolide. However, phalloidin oleate did not block the
movement, but it was employed in such a way as to only affect
cytoplasmic actin, emphasizing further that it is probable
that it is nuclear motor proteins that are affected and that
chromosome relocation is not a consequence of long-range
actions from the cytoplasmic motors [10,15].
The involvement of NM1β in whole chromosome relocation was specifically assessed by using RNA interference to
knock down MYO1C expression. Again this intervention
blocked the rapid chromosomal movement upon serum
removal, putting NM1β in the frame as the nuclear myosin
involved. From this study and studies from Belmont’s
laboratory, it appears that F-actin and NM1β are active
members of the molecular motor responsible for moving
chromatin around the nucleus [10,39].
Nuclear structure meets nuclear motor
In the cytoplasm, in order to create force, myosin 1 moves
over actin filaments and contains actin-binding domains
in its globular head and with sites in its tail domain
[15]. But how does a nuclear motor comprising actin and
myosin work? Using anti-(myosin 1β) antibodies, NM1β
is found throughout the nucleoplasm, but with a definite
concentration at nucleoli and the nuclear envelope. In
addition, actin has been described as occurring throughout
the nucleus [42]. If actin is part of a nucleoskeleton that,
although dynamic, can take tension and force, then by
NM1β binding to DNA/chromatin, genomic cargo could
be envisaged moving over short actin filaments, even if they
are localized to compartments within the nucleus. There are
some interesting binding capabilities between NM1β, actin
and other members of a nuclear structure such as nuclear
lamins. Nuclear lamins are at the nuclear envelope in the
nuclear lamina which underlies the nuclear membrane and
throughout the nucleoplasm [43,44]. Actin will bind to Atype lamins [45]. Emerin, an integral membrane protein
embedded in the nuclear membrane, is an interesting protein
with respect to its binding, since it binds A-type lamins
[46], but also NM1β and F-actin [47]. These proteins at
the nuclear envelope could be the link to the LINC (linker
of nucleoskeleton and cytoskeleton) complex that would
connect a nuclear motor to the cytoskeleton [48].
In conclusion, there a number of examples where whole
chromosomes and gene loci move rapidly and apparently
directionally through interphase nuclei in response to stimuli.
The evidence is starting to accumulate of these movements
being elicited by a nuclear motor complex that employs actin
as a filamentous base for myosins to work against. Both
actin and myosin maybe anchored at various points around
the nucleus by being bound to nucleoskeleton proteins such
as nuclear lamins and emerin. However, more evidence of
nuclear motors in moving chromatin in a directed manner is
required.
Acknowledgements
I thank Dr Christopher Eskiw and Dr Ian Kill for helpful discussions
and reading this paper before submission.
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Funding
Our work on chromosome positioning in Hutchinson–Gilford progeria
syndrome cells was supported in part by the Brunel Progeria
Research Fund.
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Received 4 August 2011
doi:10.1042/BST20110696
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