Spatial Genome Organization and Its Emerging Role as a Potential Diagnosis Tool

Abstract

In eukaryotic cells the genome is highly spatially organized. Functional relevance of higher order genome organization is implied by the fact that specific genes, and even whole chromosomes, alter spatial position in concert with functional changes within the nucleus, for example with modifications to chromatin or transcription. The exact molecular pathways that regulate spatial genome organization and the full implication to the cell of such an organization remain to be determined. However, there is a growing realization that the spatial organization of the genome can be used as a marker of disease. While global genome organization patterns remain largely conserved in disease, some genes and chromosomes occupy distinct nuclear positions in diseased cells compared to their normal counterparts, with the patterns of reorganization differing between diseases. Importantly, mapping the spatial positioning patterns of specific genomic loci can distinguish cancerous tissue from benign with high accuracy. Genome positioning is an attractive novel biomarker since additional quantitative biomarkers are urgently required in many cancer types. Current diagnostic techniques are often subjective and generally lack the ability to identify aggressive cancer from indolent, which can lead to over- or under-treatment of patients. Proof-of-principle for the use of genome positioning as a diagnostic tool has been provided based on small scale retrospective studies. Future large-scale studies are required to assess the feasibility of bringing spatial genome organization-based diagnostics to the clinical setting and to determine if the positioning patterns of specific loci can be useful biomarkers for cancer prognosis. Since spatial reorganization of the genome has been identified in multiple human diseases, it is likely that spatial genome positioning patterns as a diagnostic biomarker may be applied to many diseases.

Keywords: cancer; diagnosis; disease; gene positioning; genome organization; nuclear architecture; spatial positioning.

FIGURE 1

Non-random organization of the genome. (A,B) Whole chromosomes and genes can be visualized within interphase nuclei using FISH. (A) Chromosome 11 (green) in an interphase nucleus (blue) of the breast epithelial cell line MCF10A. (B) SPDEF (red) gene loci in normal prostate tissue (formalin-fixed paraffin embedded tissue) nuclei (blue). The spatial organization of the genome is characterized in several ways: (C) Radial positioning describes the position of a locus relative to the center and periphery of the nucleus. Gene-poor chromosomes (yellow) generally locate to the nuclear periphery, whilst gene-rich chromosomes have a preference for the nuclear interior. (D–G) Relative positioning describes the position of a locus relative to another nuclear landmark. Association frequencies can either be measured on a per cell basis (i.e., the number of nuclei in a population with at least one copy of a gene or chromosome in close proximity to the given landmark) or on a per allele basis. Examples of types of relative positioning include: (D) The position of a locus relative to another locus. The yellow and orange chromosomes are in close spatial proximity, whereas the orange and red chromosomes are distal. (E) Association with the nuclear envelope (NE). Some genes preferentially co-localize with the NE (yellow gene). (F) Association with a nuclear body such as a splicing speckle. (G) The position of gene relative its own chromosome territory. Some gene rich loci loop out of the bulk of the chromosome territory when highly expressed.

FIGURE 2

Loci-specific reorganization of the genome in disease. Certain loci adopt alternative nuclear positions in disease (tick) compared to normal cells, whilst the positions of other loci are conserved in disease (cross). Moreover, the repositioning of some loci is disease specific, and although a gene repositions in one disease, it may not in another disease. Blue, nucleus; NE, nuclear envelope; Cent., Centromere.