Elucidating chromosome territory organization during the cell cycle and in breast cancer cells
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The interchromosomal spatial positionings of a subset of human chromosomes was examined in the human breast cell line MCF10A (10A) and its malignant counterpart MCF10CA1a (CA1a) and across the cell cycle in G1 and S phase of human WI38 lung fibroblast and in 10A. The chromosomes selected cover a wide range in size and gene density and compose 30- 40% of the total human genome. Radial positioning of the chromosome territories (CT) was size dependent, but not gene density dependent. While no changes in radial positioning during the cell cycle were detected, there were stage-specific differences between cell types. There were also differences in the radial positioning of CT between 10A and CA1a, with several CT being more peripheral in CA1a. Each CT was in close proximity (interaction) with a similar number of other CT except the inactive CTXi (which had lower amount of interchromosomal contacts) and the gene rich CT17 (which had a greater amount). In contrast to all other CT, CTXi demonstrated an overall increase in interchromosomal interactions from 10A to CA1a. While the total level of interactions did not change in the majority of cases, the pairwise interactions between CT demonstrated major changes in G1 versus S and across the cell cycle. Within a cell, a pair of CT can interact in up to four possible instances (eg. CT1a-CT2a, CT1a-CT2b, CT1b-CT2a, CT1b-CT2b). The percent of cells with singular or multiple interactions between CT pairs was determined. Alterations in the pairwise interaction profiles between G1 and S phase, and between 10A and CA1a were subdivided into 5 types of altered interaction profiles: 1) overall increase, 2) overall decrease, 3) switching from 1 to ≥2, 4) vice versa, or 5) no change. While CTX was a member of CT pairs which were among the top four type 1, CT15 was a member of the top four type 3, and CT12 was a member of the top four type 4 alterations in interactions from 10A to CA1a. Furthermore, CT17 was a member of the highest pairwise CT combinations with multiple interactions. A global data mining program termed the chromatic median calculated the most probable overall association network for the entire subset of CT. This interchromosomal network was drastically altered in CA1a with only 1 of 20 shared connections. This probabilistic interchromosomal network was nearly completely different between the two cell lines. It was also strikingly altered across the cell cycle in MCF10A, but only slightly in WI38. We conclude that CT undergo multiple and preferred interactions with other CT in the cell nucleus and form preferred--albeit probabilistic--interchromosomal networks. This network of interactions is highly altered in malignant human breast cells, across the cell cycle and between cell types. It is intriguing to consider the relationship of these alterations to the corresponding changes in the gene expression program of these cell states.