Gene Clusters Reveal Fundamental Principles of Genome Folding and Transcriptional Regulation

Gene clusters generate proteome diversity required for cell fate and function. Given their genomic organization, wherein tandemly arranged genes with nearly identical promoter sequences neighbor shared enhancers, gene clusters present extreme cases of enhancer-promoter specificity, long-range enhancer-promoter communication, and chromatin compartmentalization. Here, we review recent advances in the regulation of protocadherin (Pcdh) and olfactory receptor (OR) gene clusters. These clusters present similar challenges in that cells must express a limited number of each type of gene stochastically. Probabilistic Pcdh and OR choice is accomplished through tunable enhancer-promoter interactions, but these interactions are regulated by distinct mechanisms. At the Pcdh locus, cohesin-mediated DNA loop extrusion dictates enhancer-promoter communication, whereas OR genes communicate with their enhancers through multichromosome assemblies involving the protein LDB1. In reviewing principles of Pcdh and OR regulation, we propose that gene clusters offer valuable paradigms for deciphering principles of gene expression regulation, with broad mechanistic and physiological implications for mammalian genome folding.