Nuclear position modulates long-range chromatin interactions

The human genome is non-randomly organized within the cell nucleus. Spatial mapping of genome folding by biochemical methods and imaging has revealed extensive variation in locus interaction frequencies between cells in a population and between homologs within an individual cell. Commonly used mapping approaches typically examine either the relative position of genomic sites to each other or the position of individual loci relative to nuclear landmarks. Whether the frequency of specific chromatin-chromatin interactions is affected by where in the nuclear space a locus is located is unknown. Here, we have simultaneously mapped at the single cell level the interaction frequencies and radial position of more than a hundred locus pairs using high-throughput imaging to ask whether the location within the nucleus affects interaction frequency. We find strong enrichment of many interactions at specific radial positions. Position-dependency of interactions was cell-type specific, correlated with local chromatin type, and cell-type-specific enriched associations were marked by increased variability, sometimes without a significant decrease in mean spatial distance. These observations demonstrate that the folding of the chromatin fiber, which brings genomically distant loci into proximity, and the position of that chromatin fiber relative to nuclear landmarks, are closely linked. Author summary A gene's nuclear environment is defined by its distance to other genes as well as its distance to nuclear structures such as the nuclear periphery. While both of these features have been shown to be important for gene function, they are typically studied separately. We performed the first systematic analysis comparing these two features. We determined that at the level of single chromosomes the frequency of interaction of loci is related to their location in the cell nucleus, suggesting that genome organization relative to itself and relative to nuclear landmarks are closely interwoven.