A non-random walk through the genome

Consideration of gene regulation as an interaction between the basal transcription machinery, regulators, and a segment of naked DNA containing a gene has been an extremely successful model for understanding how genetic information is read [1]. It is impossible to separate this model from the great success of modern molecular genetics. Naked DNA does not exist in nature, however. Packing DNA into the nucleus, segregating it during cell division, and making sure that it is readily available when needed for transcription is an enormously complex task for the cell and needs extensive interactions of proteins with DNA. Structural considerations have dominated our views of nuclear architecture but have not greatly influenced our concepts of transcription, other than by the broad assumption that such structure can hinder transcription. As with a building, however, the structure of the nucleus has a significant, albeit possibly subtle, influence on the work performed within it.Recent work in many different eukaryotes has suggested that genes with particular expression patterns are sometimes found in contiguous regions of the genome. We call these regions gene-expression neighborhoods; we avoid using the term 'cluster' because this usually refers to potentially co-regulated genes, regardless of their genomic position. The human eye is exceedingly adept at finding patterns and does so even in randomness (the constellations of stars are an example of patterns that humans have imposed on a random distribution). Here, we review the evidence that gene-expression neighborhoods are real. Although there are some lingering questions about the best methods for finding them and about how to avoid being tricked by spurious or artifactual patterns, the body of available evidence leaves little doubt that they exist. With a few exceptions from classical molecular biology, the regulatory mechanisms underlying gene-expression neighborhoods are not understood. Investigating these mechanisms