Gene regulation at a distance: From remote enhancers to 3D regulatory ensembles

Large-scale identification of elements associated with gene expression revealed that many of them are located extremely far from gene transcriptional start sites. We review here the growing evidence that show that distal cis-acting elements provide key instructions to genes, as genetic variation affecting them is growingly identified as an importance source of phenotypic diversity and disease. We discuss the different mechanisms that allow these elements to exert their regulatory functions, in a robust and specific manner, despite the large genomic distances separating them from their target genes. We particularly focus on the role of the structural organization of the genome in guiding such regulatory interactions.