Luis A Parada 1 , Philip G McQueen 2, and Tom Misteli 1
1 National Cancer Institute, National Institutes of Health,
Bethesda, MD 20892, USA
2 Mathematical and Statistical Laboratory, Division of
Computational Biology, Center for Information Technology, National Institutes
of Health, Bethesda, MD 20892, USA
Correspondence: Tom Misteli. E-mail: mistelit@mail.nih.gov
© 2004 Parada et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Genomes are organized in vivo in the form of chromosomes. Each chromosome
occupies a distinct nuclear subvolume in the form of a chromosome territory.
The
spatial positioning of chromosomes within the interphase nucleus is often
nonrandom.
It is unclear whether the nonrandom spatial arrangement of chromosomes
is
conserved among tissues or whether spatial genome organization is tissue-specific.
Results
Using two-dimensional and three-dimensional fluorescence in situ
hybridization we
have carried out a systematic analysis of the spatial positioning of a
subset of mouse
chromosomes in several tissues. We show that chromosomes exhibit tissue-specific
organization. Chromosomes are distributed tissue-specifically with respect
to their
position relative to the center of the nucleus and also relative to each
other. Subsets
of chromosomes form distinct types of spatial clusters in different tissues
and the
relative distance between chromosome pairs varies among tissues. Consistent
with
the notion that nonrandom spatial proximity is functionally relevant in
determining the
outcome of chromosome translocation events, we find a correlation between
tissue-specific spatial proximity and tissue-specific translocation prevalence.
Conclusions
Our results demonstrate that the spatial organization of genomes is tissue-specific
and point to a role for tissue-specific spatial genome organization in
the formation of
recurrent chromosome arrangements among tissues.
Chromosomes represent the largest structural units of eukaryotic genomes.
The
physically distinct nature of each chromosome is clearly visible during
mitosis, when
chromosomes condense and appear as separate entities. Chromosome-painting
techniques have demonstrated that chromosomes are also physically separated
during interphase, when each chromosome occupies a well defined nuclear
subvolume, referred to as a chromosome territory [1, 2].
The positioning of
chromosomes during interphase is generally nonrandom [1,
3,
4]. In cells of plants with
large genomes and of Drosophila melanogaster, centromeres and telomeres
are
positioned at opposite sides of the nucleus, giving rise to a chromosome
arrangement
known as the Rabl configuration [1, 3,
5].
In mammalian cells this pattern of genome
organization is rare; instead, the spatial organization of chromosomes
can be
described by their radial positioning relative to the center of the nucleus
[1, 3, 6]. In
human lymphocytes, the radial positioning of chromosomes correlates with
their gene
density, with gene-dense chromosomes located towards the center of the
nucleus
and gene-poor chromosomes preferentially located towards the periphery
[7, 8].
Remarkably, the preferential radial positioning of at least two chromosomes,
18 and
19, has been evolutionarily conserved over 30 million years [9].
In addition to radial
positioning, the nonrandom nature of genome organization is also reflected
in the
positioning of chromosomes relative to each other [10].
For example, in a lymphoma
cell line derived from an ATM-/- mouse, two translocated chromosomes are
preferentially positioned in close proximity to each other and the three
chromosomes
from which the translocations originated from a close-packed cluster in
normal
lymphocytes [10]. This type of nonrandom relative positioning
has been proposed to
facilitate formation of translocations by increasing the probability of
illegitimate joining
of broken chromosome ends of proximally positioned chromosomes [3,
11,
12].
While it is now well established that chromosomes are nonrandomly positioned
[3, 13, 14], it is unclear how similar
the spatial organization of the genome is in
different tissues. Analysis of the radial positions of chromosomes 18 and
19 in
different cell types failed to find significant differences [15].
Furthermore, a comparison
of the distribution of several chromosomes in tissue-cultured fibroblasts
and
lymphoblasts gave mixed results: the position of several chromosomes appeared
to
be largely conserved between the two cell types, but on the other hand,
chromosomes 6, 8, and 21 were positioned differently [7].
In both studies only radial
positioning was used as a single indicator and distributions were not directly
compared to each other by statistical means [7, 15].
In an attempt to probe the spatial
arrangement of chromosomes among tissues more systematically, we report
here the
comparative mapping of a subset of chromosomes in the cell nucleus of several
cell
types. From statistical analysis of several positioning criteria, including
radial
positioning, relative positioning, distance measurements and chromosome
cluster
analysis, we report evidence for tissue-specificity in the spatial organization
of
genomes.
We sought to investigate the nuclear position of chromosomes 1, 5, 6, 12,
14 and 15
in a range of primary cells freshly isolated from mouse tissues. We visualized
single
chromosomes by fluorescence in situ hybridization (FISH) using chromosome-specific
probes and analyzed their position in normal interphase cells containing
a diploid
complement of fluorescent signals (Figure 1).
Fig. 1: Tissue-specific radial positioning of chromosomes.
(a) FISH analysis of chromosome 5 (green)
in liver, lymphocytes and lung cell nuclei. DNA counterstaining
with DAPI is in blue.
Chromosome 5 is preferentially enriched in the nuclear interior
in liver, within the medial
nuclear subvolume in lymphocytes, and at the nuclear periphery
in lung cells. Scale bar, 2 mm.
(b) Quantitation of the radial distribution of chromosomes in different
cell types. Data was
binned in five concentric shells of equal volume designated
1 to 5 from the center of the
nucleus to the periphery. (c) Pairwise comparison of chromosome
radial distribution using
contingency table analysis. p-values < 0.05 (yellow/red)
were considered significant. Ki,
kidney; Li, liver; LL, large lung cells; Ly, lymphoblasts;
My, myeloblasts; SL, small lung cells.
Between 41 and 180 cells were analyzed per tissue.
For quantitative analysis of positioning, we first measured the distance
between the
nuclear center and the center of mass of each chromosome signal as an indicator
of
its radial position in two-dimensional (2D) projections of three-dimensional
(3D) image
stacks as previously described (Figure 1b; see also Materials
and methods) [8, 11].
The distribution profiles of chromosomes showed considerable differences
among
tissues (Figure 1b). Statistical analysis of pairwise
comparisons of the distribution of
single chromosomes using contingency table analysis among all tissues revealed
highly significant differential radial positioning (Figure
1c). Differential positioning in at
least three cell types was found for all chromosomes analyzed (Figure
1b,c). Out of 71
pairwise comparisons, 34 were statistically significant at the p < 0.05
level (Figure 1c).
Most cell types shared positioning of some, but not other chromosomes.
For example,
small lung cells and liver cells shared the position of chromosomes 12
and 14 (all
p-values > 0.5), but not of chromosomes 5, 6 and 15 (Figure
1b,c; all p-values < 3.1 ×
10-4). The most similar distribution of chromosomes was found
in cell types sharing
common differentiation pathways. Large and small lung cells shared the
distribution of
all chromosomes, and lymphoblasts and myeloblasts only differed in the
positioning of
chromosome 5 (p = 0.02) (Figure 1b,1c). As previously
reported, the radial distribution
within a cell type differed significantly among all chromosomes and most
radial
distributions were distinct from a uniform random distribution [7,
8] (Figure 1b). Similar
results were obtained in cells fixed with either paraformaldehyde or methanol.
We
conclude from these comparisons that the radial positioning of chromosomes
within
the interphase nucleus is tissue-specific.
To investigate the relative spatial relationship between chromosomes in
different cell
types, we first measured distances between the closest pair of nonhomologous
chromosomes in each cell nucleus (Table 1, Figure
2).
Table 1: Relative interchromosome distances
*Pairwise absolute measurements of distances between the closest pair of non-homologous chromosomes are expressed as relative distances normalized to the nuclear diameter to account for differences in nuclear size. †The nuclear area in an equatorial image plane was used as an indicator of nuclear size. n = number of cells analyzed.
Fig. 2: Tissue-specific distances between chromosomes. Average
minimum separations between the
most proximal pairs of nonhomologous chromosomes were compared
pairwise using the
Kolmogorov-Smirnov test.
(a) Chromosome pair 1-12; (b) 1-14; (c) 1-15; (d) 12-14; (e)
12-15; (f) 14-15; (g) 5-6. p-values < 0.05 (yellow/red)
were considered significant.
Abbreviations as in Figure 1. Between 41
and 180 cells were analyzed per tissue.
Absolute distances between
chromosomes were measured in 2D projections of 3D image stacks and expressed
as
relative distances normalized to the nuclear diameter to take into account
the
variations in nuclear size among tissues. We find significant differences
in the physical
separation of six out of seven chromosome pairs among cell types (Table
1, Figure 2).
For example, the closest homologs of chromosomes 12 and 14 were separated
by
24.5% of the nuclear diameter in lymphocytes, whereas they were only separated
by
19.4% in liver cells. This difference is statistically highly significant
in a
Kolmogorov-Smirnov test (p = 1.1 × 10-6). Similarly, chromosomes
5 and 6 were
separated by 25.0% of nuclear diameter in small lung cells, but by only
17.7% in liver
cells (p = 1.3 × 10-3) (Table 1, Figure
2). While most chromosome pairs had
statistically distinct separation distances in several tissues, chromosomes
1 and 12
appeared to be more conserved in their relative positions (Figure
2). The differences
in chromosome distances were not due to differences in the size or shape
of the cell
nucleus, as indicated by the shorter interchromosomal distances in kidney
or large
lung cells compared to lymphocytes, whose nuclei are significantly smaller
(Table 1)
[15]. Furthermore, no correlation between distances
between chromosomes and
nucleus size was observed between large and small lung cells (Table
1).
A second, more direct criterion to test the relative positioning of chromosomes
relative
to each other was used. Chromosomes 12, 14 and 15 have previously been
reported
to have nonrandom relative positioning in lymphocytes where they form a
close-packed triplet cluster [10]. We used the spatial
clustering of these chromosomes
to further probe the positioning of chromosomes relative to each other
among tissues.
Fig. 3: Tissue-specific relative positioning of chromosomes
12, 14 and 15. Quantitation of triplet
cluster formation by determining for each tissue type the
percentage of cells containing (a) no
12-14-15 triplet clusters, (b) a single triplet cluster of
exactly one chromosome 12, 14 and 15,
(c) a single cluster of a pair of homologues and one additional
chromosome, or (d) a cluster of
homologues and more than one additional chromosome. Expected
values based on random
distribution of chromosomes are indicated by a dashed line.
Between 41 and 180 cells were
analyzed per tissue. (e) FISH analysis of different cell types
for chromosome 12 (red), 14
(blue), and 15 (green).
Distinct preferential cluster types are found in different cell types.
Scale
bar, 1.8 mm.
For each tissue, we determined the percentages of cells containing: no
12-14-15
triplet clusters (Figure 3a); a single triplet cluster
containing exactly one chromosome
12, 14 and 15 (Figure 3b); a single cluster made up of
a pair of homologs and one
additional chromosome (Figure 3c); or a cluster containing
a pair of homologs and
more than one additional chromosome (Figure 3d). As previously
described, a cluster
was defined as a triplet where all chromosomes are separated by less than
30% of
the nuclear diameter [10]. Statistically significant
quantitative differences in the
occurrence of the four types of chromosome clusters were detected among
tissues by
contingency table analysis (Figure 3a-d, and see Additional
data file 1).
Formation of distinct types of clusters was also evident by qualitative
inspection
(Figure 3e). Almost 50% of large and small lung cells
contained no obvious clusters
(Figure 3a). In contrast only around 20% of kidney and
liver cells did not contain
clusters (Figure 3a). About 30% of lymphocytes and myeloblasts
did not contain
clusters (Figure 3a). As previously reported, clusters
containing exactly one copy of
chromosome 12, 14 and 15 were prevalent in lymphocytes with 35% of cells
containing such a cluster, but only 13% of liver cells, 17% of small lung
cells and 19%
of kidney cells contained such a cluster (Figure 3b;
0.01<p < 0.05). Clusters containing
one homolog pair were more evenly distributed among tissues, but significant
differences were still found. Almost 30% of liver cells, but only 12-15%
of small and
large lung cells and lymphocytes contained this type of arrangement (Figure
3c; p <
0.03 for all comparisons). Similarly, clusters simultaneously containing
a nonhomolog
and a homolog pair were present at differentially frequencies among tissues.
They
were found in around 36% of kidney and liver cells, but only in 11% of
large lung cells
(4.2 × 10-4 <p < 5.9 × 10-4) and
15% in lymphocytes (Figure 3d; 0.08 <p < 0.09).
Statistical tests for triplet formation by contingency table analysis showed
that the
majority of triplets were found at frequencies different from those expected
on the
basis of a random distribution of chromosomes (Figure 3a-e,
and see Additional data
file 1).
To test whether these differences in chromosome clusters were limited to
the
12-14-15 triplet or were a general feature, we analyzed clusters containing
chromosomes 1-12-14, 1-14-15 and 1-12-15. Statistically significant differential
occurrence of relative positioning of chromosomes in triplets was found
for all of these
chromosome combinations (see Additional data files 2-4).
Similar results were
obtained when close chromosome pairs were defined as separated by 20% of
the
nuclear diameter (data not shown). These observations strongly suggest
that the
positioning of chromosomes relative to each other differs among tissues.
The degree of relative spatial proximity of chromosomes has previously
been
implicated to be functionally relevant in formation of chromosome translocations
in
blood cancers [3, 10-12, 16-18].
As translocations from different tumor tissues,
including both blood and epithelial tumors, are frequently characterized
by
translocations between distinct sets of chromosomes [19],
we asked whether the
observed differences in spatial chromosome arrangements may explain the
formation
of tissue-specific translocations. To directly test this hypothesis we
took advantage of
the differential translocation behavior of chromosome pairs 5, 6 and 12,
15 in mouse
lymphocytes and liver. Translocations between chromosomes 5 and 6 frequently
occur
in mouse hepatomas but are not found in lymphomas; conversely, translocations
between 12 and 15 are prevalent in lymphomas but not in hepatomas [20,
21].
Qualitative inspection indicated that in hepatocytes, the translocation-prone
chromosomes 5 and 6 were more frequently in close physical proximity than
non-translocating chromosomes 12 and 15 (Figure 4a).
Fig. 4: Tissue-specific relative chromosome positioning correlates with tissue specific translocation frequency.
(a) FISH analysis of chromosome 5 (green),
6 (red), 12 (green)
and 15 (red) in
hepatocytes or lymphocytes. Arrowheads indicate proximal pairs.
Scale bar, 2 mm. Pairs of
chromosomes 5-6 are more frequent than pairs of chromosomes
12-15 in hepatocytes,
whereas the opposite is true in lymphocytes.
(b) Determination of the percentage of
hepatocytes or lymphocytes containing at least one 5-6 or
12-15 pair. The likelihood of pair
formation correlates with the observed tissue-specific translocation
frequency among these
chromosomes. Dotted lines represent expected values based
on a uniform random
distribution. Note that the expectation value of contingency
tables is dependent on the
number of analyzed cells. For analysis of 5-6 pairing, 83
hepatocytes and 118 lymphocytes
were analyzed. For analysis of 12-15 pairing, 158 hepatocytes
and 88 lymphocytes were
analyzed.
Our observations provide evidence for tissue-specific spatial organization
of genomes
in the interphase cell nucleus. While we show here that a subset of mouse
chromosomes exhibits differential nuclear positioning among tissues, we
suspect that
differential spatial organization is a general feature of most chromosomes.
As radial
positioning of some chromosomes is evolutionarily conserved, tissue-specificity
is likely
to occur in other species as well [9]. Patterns of chromosome
arrangements were
more similar among tissue types that share differentiation pathways, suggesting
that
chromosome positioning might be established during differentiation. As
previously
reported [15], differences in chromosomes positioning
were not due to variation in cell
size or shape among tissues, as, for example, the morphologically extremely
distinct
small and large lung cells showed similar distribution patterns. Furthermore,
although
changes in chromosome positioning have been reported for the G0/G1 transition,
our
observed differences were unlikely to be due to cell-cycle effects, as
chromosome
positioning does not significantly change during interphase in cycling
cells [22-25]. We
suspect that our estimates of the differences in chromosome positions might
be an
underestimate as it is possible that our isolated cell populations contain
several cell
types, which might exhibit distinct chromosome positions. A more detailed
future
analysis of distinct cell types in the context of intact tissues will be
insightful to
address this issue.
The functional significance of tissue-specific spatial genome organization
in gene
expression remains unclear. It is possible that the positioning of chromosomes
into
particular nuclear neighborhoods might expose gene loci to local concentrations
of
specific regulatory factors or might place loci into a transcriptionally
silent
heterochromatic environment [3, 26, 27].
This model is consistent with the observed
peripherization of immunoglobulin loci during lymphocyte development and
repositioning of several differentiation-stage-specific gene loci away
from centromeres
during B-cell differentiation [28-30]. Although a previous
analysis of radiation-induced
random translocations in human lymphocytes yielded no positive evidence
for
preferential relative positioning of chromosomes [4],
several reports support a
functional link between nonrandom relative positioning and formation of
translocations. A number of translocation-prone chromosomes and gene loci
have
been shown to be in preferential spatial proximity to their translocation
partners in
normal cells before translocation events [10-12, 14,
16,
17]. Our observations support
this notion and extend it by demonstrating a correlation between tissue-specific
spatial organization and tissue-specific translocation frequency. This
result suggests
that the distinct spatial organization of genomes in normal tissues contributes
to the
tissue-specificity of prevalent translocations.
It is unclear at present how patterns of chromosome arrangements are established
and maintained. One possibility is that the nucleus contains specific structural
components that determine genome organization. Tissue-specificity of genome
organization could be established by regulated expression of structural
proteins such
SATB1, a thymocyte-specific protein that has been proposed to regulate
thymocyte-specific genes by tethering chromatin regions onto a structural
nuclear
scaffold [31]. An intriguing alternative possibility
is that the transcriptional status of
chromosome regions affects their structural properties and that the collective
transcriptional activity of a genome thus determines its arrangement in
a
self-organizing manner based on the physical properties of the chromatin
and the
interacting polymerases [32]. In our case, chromosomes
12 and 15 contain
nucleolar-organizing centers which might facilitate the preferential nonrandom
association of these chromosomes. Our observation of similarities in genome
organization in cell types with shared differentiation pathways is consistent
with such
a self-organization model. Regardless of how the patterns are established,
our
description of tissue-specific spatial genome patterns should be of use
in further
experimental tests of these models as well as in understanding the functions
and
mechanisms of nonrandom spatial genome organization.
Cell preparation
C57BL/6 mice (4-8 weeks old) were sacrificed and the relevant tissues recovered.
For
lung and kidney samples the tissue was washed in RPMI 1640 medium and the
tissue
minced with scalpels and enzymatically disaggregated by collagenase type
IV. The
resulting cell suspension was washed twice by centrifugation in RPMI 1640
medium.
Cells were successively plated four times at 60-min intervals in medium
consisting of
Dulbecco's MEM, supplemented with 10% fetal bovine serum, penicillin (100
IU/ml),
streptomycin (0.2 mg/ml), hydrocortisone (0.5 mg/ml),
dibutyryl cAMP (10 nM), and 1%
insulin/transferrin/sodium selenite. The epithelial-enriched cell suspension
was
seeded onto glass coverslips. After 24 h the coverslips were processed
for FISH
analysis. Lymphocytes and granulocytes were isolated from spleen and thymus
by
differential centrifugation in a gradient of Ficoll/sodium diatrizoate.
Hepatocytes were
isolated by two-step collagenase perfusion of the liver followed by isodensity
centrifugation in Percoll. Cells were washed by centrifugation in isotonic
phosphate-buffered solution and cytocentrifuged (105 cells/ml)
onto glass slides and
fixed in 4% paraformaldehyde.
Chromosome painting
Detailed protocols for FISH and probe generation are available online [33].
Briefly,
slides were hybridized for 48 h at 37°C in a moist chamber with a combination
of
three painting probes at a time. Probes were prepared from flow-sorted
chromosomes
by degenerate oligonucleotide-primed polymerase chain reaction (PCR) using
biotin,
digoxigenin or Spectrum Red deoxyuridine nucleotides for labeling. Biotin
and
digoxigenin-labeled probes were detected with streptavidin conjugated to
Cy5 and
FITC-conjugated sheep anti-digoxigenin antibodies respectively. Specimens
were
examined with a Nikon Eclipse E800 microscope equipped with epifluorescence
optics
and a Photometrics MicroMax cooled CCD camera (1,300 × 1,300 array,
6.7 mm pixel
size, 5 MHz, image pixel size 80 nm).
Positioning measurements
Images of triple-labeled cell nuclei were generated and analyzed using
MetaMorph
Imaging System 4.6 (Universal Imaging). All measurements were performed
on
maximum projections of 10 focal planes covering the entire nucleus. All
measurements
were done on unprocessed images without thresholding. For distance analysis
the
perimeter of each cell as well as each chromosome were manually drawn on
the
maximum projection and the center of mass determined automatically using
MetaMorph software. Chromosomes in the projections were visually compared
to the
single focal planes to verify that the regions were representative of the
entire
chromosome. The mean nuclear radii, and the center of mass of each chromosome
and nucleus were measured using MetaMorph software. Nuclear radii (Rn)
and
diameters (Dn) were calculated from Rn = (A/pi)^
0.5, where (A) is the nuclear pixel
area. Radial chromosome positions were calculated as [(Ch:C)/Rn
× 100], where
(Ch:C) is the distance from the center of an individual chromosome to the
nuclear
center. Cell nuclei were subdivided in five concentric shells of equal
volume designated
1 to 5 from the center of the nucleus to the periphery. To measure relative
positioning, the absolute spatial separations between chromosome pair centers
of
mass (Ch1:Ch2) were normalized as a fraction of nuclear
diameter [(Ch1:Ch2)/Dn ×
100] to account for natural variations in nuclear size. For measurements
of radial
positioning both homologs were scored separately. For distance measurements
the
closest non-homolog pair was measured for each possible chromosome combination.
Statistical analysis
Analysis of radial and relative positioning were essentially performed
as previously
described [10, 11]. To characterize specific trends
in the radial distribution of
chromosomes, we conducted contingency table analysis with the null hypothesis
that
a given chromosome has the same radial distribution in the two cell types
being
compared [10, 11, 34, 35]. The bins
used to generate contingency tables were defined
by the following boundaries: 0.0-33.98%, 33.98-48.79%, 49.79-61.51%,
61.61-73.91% and > 73.91% nuclear radius. Bins defined in this manner represent
volumes with equal probability of containing the same number of chromosomes
assuming a uniform random distribution of 40 spherical chromosomes of excluding
volume with a radius of 10% of the nuclear volume in a spherical nucleus.
To test for
differences in average minimum separation of chromosome pairs between cell
types
we applied the Kolmogorov-Smirnov test [36]. To test
for differences in proximal triplet
formation, we constructed contingency tables for the frequencies of the
experimentally observed four categories of chromosome arrangements [34,
35].
Triplets were defined as a collection of three chromosome pairs all separated
by less
than 30% of nuclear diameter [10]. The contingency table
analysis tested the null
hypothesis that all four categories of chromosome arrangements are equally
likely and
independent of the cell type. To determine tissue-specific proximity of
translocation
partners we determined the frequencies of cells containing at least one
close pair of
either 5-6 or 12-15 in lymphocytes and hepatocytes as previously described
[11]. We
defined a close pair as two chromosomes located at a distance not larger
that 20% of
the nuclear diameter. Frequencies of pair formation were analyzed analogously
to the
triplet analysis using the null hypothesis that the number of close pairs
in a given cell
type is independent of the identities of the chromosomes. All analyses
were done
using standard algorithms coded in Java. For all experiments data from
at least three
independent experiments was pooled.
Additional data files: http://genomebiology.com/2004/5/7/r44/suppl/s1
Additional data file 1: Contingency table for chromosomes 12, 14, and 15 triplet formation
Additional data file 2: Contingency table for chromosomes 1, 12 and 14 triplet formation
Additional data file 3: Contingency table for chromosomes 1, 12 and 15 triplet formation
Additional data file 4: Contingency table for chromosomes 1, 14 and 15 triplet formation
We thank Jeff Roix for critical reading of the manuscript. T.M. is a fellow of the Keith. R. Porter Endowment for Cell Biology.
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In this new study by Luis Parada, Philip McQueen, and Tom Misteli,
we see that mouse chromosomes associate during interphase in non-random
tissue-specific patterns. These patterns can be measured from the nucleus
center or from one chromosome to one or more other chromosomes. These data
provide a strong suggestion that the transcription sites on each
chromosome are interacting with transcription sites on other chromosomes,
perhaps in a necessary manner.
1. Hovsepian JA, and Frenster JH, "Euchromatin as an Extensile Force within Mammalian Cell Nuclei".
2. Kreth G, Finsterle J, von Hase J, Cremer M, and Cremer C, "Radial Arrangement of Chromosome Territories in Human Cell Nuclei: A Computer Model Approach Based on Gene Density Indicates a Probabilistic Global Positioning Code".
3. Chambeyron S, and Bickmore WA, "Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription".
4. Frenster JH, and Hovsepian JA, "Activator RNA Exchange during Interphase Chromatin Reprogramming".
Links to
Euchromatin Activator RNA Reviews:
Links to
Euchromatin Activator RNA Research:
Links to Ultrastructural
Probes of DNase I-Sensitive Sites:
Links to
RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma
Immuno-Pathology:
Links to Activated
T-Lymphocyte Immunotherapy:
Links to Medical
Systems Biology:
Links to RNA-Induced
Epigenetics:
Links to Reprogramming
and Neoplasia:
"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".
