Abstract
The interchromosomal organization of a subset of human chromosomes (#1, 4, 11, 12, 16, 17, and 18) was examined in G1 and S phase of human WI38 lung fibroblast and MCF10A breast epithelial cells. Radial positioning of the chromosome territories (CTs) was independent of gene density, but size dependent. While no changes in radial positioning during the cell cycle were detected, there were stage-specific differences between cell types. Each CT was in close proximity (interaction) with a similar number of other CT except the gene rich CT17 which had significantly more interactions. Furthermore, CT17 was a member of the highest pairwise CT combinations with multiple interactions. Major differences were detected in the pairwise interaction profiles of MCF10A versus WI38 including cell cycle alterations from G1 to S. These alterations in interaction profiles were subdivided into five types: overall increase, overall decrease, switching from 1 to ≥2 interactions, vice versa, or no change. A global data mining program termed the chromatic median determined the most probable overall association network for the entire subset of CT. 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 nucleus and form preferred -albeit probabilistic- interchromosomal networks. This network of interactions is altered 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 across the cell cycle and in different cell types.
Highlights
At the highest structural level, chromosomes form discrete bodies termed chromosome territories (CT) [1,2,3,4,5,6]
Our overall understanding of CT organization and their interchromosomal interactions, is very limited. We have addressed this issue by combining the approaches of 3D FISH, an extensive computational program that enables us to obtain precise measurements of CT interactions in 3-D and a novel global data mining program that evaluates the overall arrangement of all the interacting CT. 7 CT pairs ranging in size and gene density were examined in two different human cell types
Our findings demonstrate that: 1) there are preferred interchromosomal networks that are altered across the cell cycle; 2) these alterations are cell type specific; 3) all the CT interact with a similar number of other CT with the exception of the gene rich CT17 which interacts with significantly more CT; and 4) multiple interactions in the four possible combinations between CT pairs are far more common than in random simulations
Summary
At the highest structural level, chromosomes form discrete bodies termed chromosome territories (CT) [1,2,3,4,5,6]. Chromosomes that contain the nucleolar organizing regions preferentially interact with nucleoli [16,17]. While many studies have revealed a probabilistic nonrandom radial organization of CT within the nucleus [18] for review], fewer reports have investigated whether there are specific interchromosomal arrangements [19,20,21] and whether these are altered in different cell and tissue types [22,23,24,25] during cell differentiation and development [26] and in cancer [27,28,29]. The predominant method for studying CT organization has involved CT centers of gravity which may or may not reflect interactions of these CT at their borders. Due to technical limitations, the vast majority of these studies have been limited to three or less CT pairs per nucleus
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