Why the activity of a gene depends on its neighbors

•Sixty years ago gene position was seen to be a major determinant of gene activity.•Nowadays, position effects are no longer central to current discussions.•We describe a simple view of how position in 1D sequence and 3D nuclear space underlies expression.•Enhancers, silencers, insulators, barriers, and boundaries are seen to be functionally similar.

Sixty years ago, the position of a gene on a chromosome was seen to be a major determinant of gene activity; however, position effects are rarely central to current discussions of gene expression. We describe a comprehensive and simplifying view of how position in 1D sequence and 3D nuclear space underlies expression. We suggest that apparently-different regulatory motifs including enhancers, silencers, insulators, barriers, and boundaries act similarly – they are active promoters that tether target genes close to, or distant from, appropriate transcription sites or ‘factories’. We also suggest that any active transcription unit regulates the firing of its neighbors – and thus can be categorized as one or other type of motif; this is consistent with expression quantitative trait loci (eQTLs) being widely dispersed.