Large-scale probabilistic 3D organization of human chromosome territories

Abstract

There is growing evidence that chromosome territories (CT) have a probabilistic non-random arrangement within the cell nucleus of mammalian cells including radial positioning and preferred patterns of interchromosomal interactions that are cell-type specific. While it is generally assumed that the three-dimensional (3D) arrangement of genes within the CT is linked to genomic regulation, the degree of non-random organization of individual CT remains unclear. As a first step to elucidating the global 3D organization (topology) of individual CT, we performed multi-color fluorescence in situ hybridization using six probes extending across each chromosome in human WI38 lung fibroblasts. Six CT were selected ranging in size and gene density (1, 4, 12, 17, 18 and X). In-house computational geometric algorithms were applied to measure the 3D distances between every combination of probes and to elucidate data-mined structural patterns. Our findings demonstrate a high degree of non-random arrangement of individual CT that vary from chromosome to chromosome and display distinct changes during the cell cycle. Application of a classic, well-defined data mining and pattern recognition approach termed the 'k-means' generated 3D models for the best fit arrangement of each chromosome. These predicted models correlated well with the detailed distance measurements and analysis. We propose that the unique 3D topology of each CT and characteristic changes during the cell cycle provide the structural framework for the global gene expression programs of the individual chromosomes.

Chromosome territories and the global regulation of the genome

“…Thus, when measured at large genomic separations, each CT displays a different profile of genomic to spatial distances that are nonrandom. An exception was CT 17 whose MSD/FR plots were similar to its random simulations with only a small portion displaying nonrandom folding …”

“…The average distance between labeled DNA probes ranged from ~15 to 60 Mbp. At these large Mbp distances between probes, MSD analysis along with studies of the folding ratios (FRs) across the CT demonstrated that each CT had a specific folding pattern with some limited alterations across the cell cycle . Random simulation plots of all the CT except CT 17 were very different from the actual CT determinations and uniformly showed little or no changes in MSD or FRs across the entire simulated CT.…”

“…These investigations demonstrated a large increase in MSD within ∼2 Mbp followed by a much more gradual increase in MSD extending the length of each chromosome . A more recent study combined the tools of 3‐D microscopy, multi‐FISH, computer imaging, and computational geometric analysis to analyze six labeled regions spanning each CT in the G1 and S phase of WI38 normal diploid human fibroblasts . The six CT investigated (1, 4, 12, 17, 18, X) are representative of both the range of gene densities and CT size in the genome.…”

Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer

“…Physiological control of gene expression is dependent on chromatin context and requires timely and dynamic interactions between transcription factors and coregulatory machinery that reside in specialized subnuclear microenvironments . Multiple levels of nuclear organization functionally contribute to biological control and are perturbed in cancer . Morphologically, cancer nuclei are generally larger, more irregularly shaped, and have altered subnuclear structures .…”

Super‐resolution structure of DNA significantly differs in buccal cells of controls and Alzheimer's patients

“…These technological advances have enabled today's researchers to add detail to Boveri's concept. We have learned that chromosome territories are the structure of chromosomes in interphase nuclei (Cremer & Cremer, ; Cremer et al, ; Fritz et al, ; Sehgal et al, ) and were able to depict all of them together using successive hybridizations (Bolzer et al, ). We learned that chromosome positions are conserved during evolution (Tanabe et al, ) and that gene‐poor and gene‐dense chromosomes have their specific nuclear location in human cells (Tanabe et al, ).…”