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. 2010 May;20(5):554-64.
doi: 10.1101/gr.103622.109. Epub 2010 Mar 8.

The Effect of Translocation-Induced Nuclear Reorganization on Gene Expression

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Free PMC article

The Effect of Translocation-Induced Nuclear Reorganization on Gene Expression

Louise Harewood et al. Genome Res. .
Free PMC article

Abstract

Translocations are known to affect the expression of genes at the breakpoints and, in the case of unbalanced translocations, alter the gene copy number. However, a comprehensive understanding of the functional impact of this class of variation is lacking. Here, we have studied the effect of balanced chromosomal rearrangements on gene expression by comparing the transcriptomes of cell lines from controls and individuals with the t(11;22)(q23;q11) translocation. The number of differentially expressed transcripts between translocation-carrying and control cohorts is significantly higher than that observed between control samples alone, suggesting that balanced rearrangements have a greater effect on gene expression than normal variation. Many of the affected genes are located along the length of the derived chromosome 11. We show that this chromosome is concomitantly altered in its spatial organization, occupying a more central position in the nucleus than its nonrearranged counterpart. Derivative 22-mapping chromosome 22 genes, on the other hand, remain in their usual environment. Our results are consistent with recent studies that experimentally altered nuclear organization, and indicated that nuclear position plays a functional role in regulating the expression of some genes in mammalian cells. Our study suggests that chromosomal translocations can result in hitherto unforeseen, large-scale changes in gene expression that are the consequence of alterations in normal chromosome territory positioning. This has consequences for the patterns of gene expression change seen during tumorigenesis-associated genome instability and during the karyotype changes that lead to speciation.

Figures

Figure 1.
Figure 1.
Mapping of t(11;22) and Emanuel syndrome differentially expressed genes. Ensembl Karyoview ideograms showing the chromosomal location of the top 100 differentially expressed genes between Emanuel patients (unbalanced) and controls (A–D) and between carriers of the balanced t(11;22) translocation and controls (E–G). Complete karyograms are shown in A and E, while detailed views of chromosomes 11 and 22 are shown in B and F, and C and G, respectively. The derivative chromosome 22, which corresponds to the trisomic regions in Emanuel syndrome patients, is shown in D. The blue lines indicate the translocation breakpoints. Green arrowheads mark the genes showing an increase in expression in cell lines from Emanuel syndrome patients (A–D) and translocation carriers (E–G), while red arrowheads depict those showing a decrease.
Figure 2.
Figure 2.
Numbers of differentially expressed transcripts between t(11;22) carriers and control individuals. Graphs showing the number of differentially expressed transcripts between the studied cohorts identified with variable P-value thresholds and mapping on all (A) or autosomal only (B) chromosomes. Axes are in log scale. The following comparisons are shown: balanced [i.e., t(11;22) carriers] versus control cohorts (red line; nine vs. 13 samples), male versus female cohorts (blue line; six vs. 16 samples), young versus old cohorts (green line; nine vs. 13), and unbalanced (Emanuel syndrome patients, with partial trisomy 11 and 22) versus full-genome complement cohorts (unbalanced [four] vs. others [22]; orange line). Note that the sex and aneuploid/euploid comparisons are provided for information only. They involve different numbers of samples and therefore cannot be directly compared with the “balanced versus control” statistics or to the permutation distribution (see below). These two comparisons and the age comparison are compared with their own permutation results in Supplemental Figures S3, S4, and S5. The gray lines and shaded area represent 50%, 70%, 90%, and 95% of the permutation distribution (nine vs. 13; see main text for details). We observe that the number of transcripts differentially expressed between the control and the balanced cohorts follows the line demarcating 95% of the permutations, suggesting that t(11;22) carriers are at one tail of the distribution of transcriptome profiles.
Figure 3.
Figure 3.
Nuclear position of normal and derivative chromosome territories in t(11;22) cells and control cell lines. BAC coordinates are shown in Table 1. (A) Chromosome ideograms and schematic representation of the regions recognized by FISH probes used to distinguish the normal and derivative chromosome 11s, and an example of FISH on lymphoblastoid cells from a t(11;22) carrier. (Green) Chromosome 11 paint; (red) BAC RP11-422P18. DNA is counterstained with DAPI (blue). In nuclei of cells carrying the balanced t(11;22), the normal HSA11 is marked solely by the green chromosome paint signal, whereas the green painted territory for the derivative chromosome 11 is also associated with a red BAC hybridization signal. The normal HSA22 is indicated by a lone red BAC signal. (B) As in A, but chromosome 11 paint is in red and BAC RP11-93E4 is in green. In nuclei of cells carrying the balanced t(11;22), the normal HSA11 is marked by the red chromosome paint signal associated with a green BAC hybridization signal, whereas the derivative chromosome 11 is marked solely by the red painted territory. The derivative chromosome 22 is indicated by a lone green BAC signal. (C) Mean (+ SEM) percent of chromosome 11 paint hybridization signal present in five shells of equal area eroded from the edge (shell 1) to the center (shell 5) of the nucleus in seven control cell lines of normal karyotype (left) and four t(11;22) cell lines (right), showing the relative positions of the normal (blue) and derivative chromosome 11 (green). n = 40–50 nuclei each for each cell lines. The derivative 11 territory is shifted to a more central position in the nucleus compared with the normal 11. (D) As in C, but using BAC RP11-422P18 on four normal cell lines (left) and four t(11;22) cell lines (right) to compare positioning of the normal chromosome 22 (red) from that of the derivative 11 (green). The BAC signal on the derivative 11 is situated in a more peripheral position than that on the normal chromosome 22. (E) As in C, but using BAC RP11-93E4 on four normal cell lines (left) and five t(11;22) cell lines (right) to compare positioning of the normal chromosome 11 (blue) from that of the derivative 22 (yellow). The BAC signal on the derivative 22 is situated in a more central position than that on the normal chromosome 11.
Figure 4.
Figure 4.
Nuclear position of chromosome 17 territories and fosmids covering differentially expressed genes in normal and t(11;22) cells. The fosmid coordinates and mapping positions are shown in Table 1 and Supplemental Figure S6, respectively. (A) Mean (+SEM) percent of chromosome 17 paint hybridization signal present in five shells of equal area eroded from the edge (shell 1) to the center (shell 5) of the nucleus in four control cell lines of normal karyotype (dark purple) and five t(11;22) cell lines (light purple) showing the relative positions of the chromosome 17s. n = 40–50 nuclei each for each cell lines. The chromosome 17 territory is shifted to a more peripheral position in nuclei from balanced translocation carriers as compared to controls. (B) Mean (+SEM) percent of the hybridization signal of chromosome 9q21.32 fosmid G248P81402D5 (D5) in four control cell lines of normal karyotype (dark blue) and four t(11;22) cell lines (pink) showing the relative positions of the fosmid. The fosmid signal is shifted to a slightly more peripheral position in nuclei from balanced cell lines as compared with controls. (C) As in B, but using fosmid G248P8942D11 (D11) on three control cell lines of normal karyotype (right) and four t(11;22) cell lines (left), showing the relative positions of the fosmid on the normal 11 (blue) and on the derivative chromosome 11 (green). The fosmid signal on the derivative 11 is shifted to a slightly more peripheral position than that on the normal 11. (D) As in B, but using fosmid G248P84992F11 (F11) on three control cell lines (left) and four t(11;22) cell lines (right), showing the relative positions of the normal 22 (red) and the derivative 11 (green). The fosmid signal on the derivative 11 is shifted to a slightly more central position than that on the normal 22. (E) As in B, but using fosmid G248P87917B7 (B7) on four control cell lines (left) and five t(11;22) cell lines (right), showing the relative positions of the normal 22 (red) and the derivative 11 (green). This fosmid covers a gene that does not show any differential expression between balanced translocation carriers and controls and the fosmid signal on the derivative 11 shows no difference in position compared with that on the normal 22.

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