Coordinate Gene Regulation during Hematopoiesis Is Related to Genomic Organization

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Abstract
Gene loci are found in nuclear subcompartments that are related to their expression status. For instance, silent genes are often localized to heterochromatin and the nuclear periphery, whereas active genes tend to be found in the nuclear center. Evidence also suggests that chromosomes may be specifically positioned within the nucleus; however, the nature of this organization and how it is achieved are not yet fully understood. To examine whether gene regulation is related to a discernible pattern of genomic organization, we analyzed the linear arrangement of co-regulated genes along chromosomes and determined the organization of chromosomes during the differentiation of a hematopoietic progenitor to erythroid and neutrophil cell types. Our analysis reveals that there is a significant tendency for co-regulated genes to be proximal, which is related to the association of homologous chromosomes and the spatial juxtaposition of lineage-specific gene domains. We suggest that proximity in the form of chromosomal gene distribution and homolog association may be the basis for organizing the genome for coordinate gene regulation during cellular differentiation. How are genomes—and the chromosomes that comprise them—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 organized—with proximity playing a key role—to facilitate coordinated gene regulation during cellular differentiation.