Chromosome territories, nuclear architecture and gene regulation in mammalian cells

The expression of genes is regulated at many levels. Perhaps the area in which least is known is how nuclear organization influences gene expression. Studies of higher-order chromatin arrangements and their dynamic interactions with other nuclear components have been boosted by recent technical advances. The emerging view is that chromosomes are compartmentalized into discrete territories. The location of a gene within a chromosome territory seems to influence its access to the machinery responsible for specific nuclear functions, such as transcription and splicing. This view is consistent with a topological model for gene regulation. Key Points Chromosomes occupy discrete territories in the cell nucleus and contain distinct chromosome-arm and chromosome-band domains. Chromosome territories (CTs) with different gene densities occupy distinct nuclear positions. Gene-poor, mid-to-late-replicating chromatin is enriched in nuclear compartments that are located at the nuclear periphery and at the perinucleolar region. A compartment for gene-dense, early-replicating chromatin is separated from the compartments for mid-to-late-replicating chromatin. Chromatin domains with a DNA content of ∼1 Mb can be detected in nuclei during interphase and in non-cycling cells. The interchromatin compartment (IC) contains various types of non-chromatin domains with factors for transcription, splicing, DNA replication and repair. The CT–IC model predicts that a specific topological relationship between the IC and chromatin domains is essential for gene regulation. The transcriptional status of genes correlates with gene positioning in CTs. A dynamic repositioning of genes with respect to centromeric heterochromatin has a role in gene silencing and activation. Various computer models of CTs and nuclear architecture make different predictions that can be validated by experimental tests. Comprehensive understanding of gene regulation requires much more detailed knowledge of gene expression in the context of nuclear architecture and organization.