The importance of considering regulatory domains in genome-wide analyses – the nearest gene is often wrong!

The expression of a large number of genes is regulated by regulatory elements that are located far away from their promoters. Identifying which gene is the target of a specific regulatory element or is affected by a non-coding mutation is often accomplished by assigning these regions to the nearest gene in the genome. However, this heuristic ignores key features of genome organisation and gene regulation; in that the genome is partitioned into regulatory domains, which at some loci directly coincide with the span of topologically associated domains (TADs), and that genes are regulated by enhancers located throughout these regions, even across intervening genes. In this review, we examine the results from genome-wide studies using chromosome conformation capture technologies and from those dissecting individual gene regulatory domains, to highlight that the phenomenon of enhancer skipping is pervasive and affects multiple types of genes. We discuss how simply assigning a genomic region of interest to its nearest gene is problematic and often leads to incorrect predictions and highlight that where possible information on both the conservation and topological organisation of the genome should be used to generate better hypotheses. The article has an associated Future Leader to Watch interview.