How are genomesâ€”and the chromosomes that comprise themâ€”organized in the eukaryotic nucleus? This long-standing question in cell biology has gained renewed interest due to observations that gene regulation is correlated with the nonrandom distribution of gene loci linearly along chromosomes and spatially within the nucleus. We have used an in vitro model of cellular differentiation to test the hypothesis that there is an inherent organization of the genome related to coordinate gene regulation. Our analysis reveals that during the differentiation of a murine hematopoietic (blood-forming cell) progenitor to derived cell types, co-regulated genes have a marked tendency to be proximal along chromosomes in the form of clusters (of two and three genes) and large-scale domains. Overall gene expression is also spatially proximal, with a pronounced concentration in the nuclear center. The chromosomes themselves parallel this organization of gene activity, with chromosome territories localizing primarily in the interior of the nucleus. Surprisingly, we found that homologous chromosomes have a tendency to be associated, the extent of which is related to the number of co-regulated genes residing on the particular chromosome. Furthermore, individual gene domains display lineage-specific proximity according to their co-regulation. Our study supports the idea that the eukaryotic nucleus is broadly organizedâ€”with proximity playing a key roleâ€”to facilitate coordinated gene regulation during cellular differentiation.
Received: July 10, 2006; Accepted: September 25, 2007; Published: November 20, 2007