The genes in the human β-globin cluster are co-regulated by a single control region or master cis-regulatory site. Surprisingly, few other master regulators have been identified, although they are suspected to be important in disease. In the past, variants in master regulatory sites have been used to identify defects in the expression of single genes. Tong et al. have expanded the reach of such studies to identify and investigate the effect of variants on the co-regulation of multiple genes. Further analysis of the three-dimensional structure of the genome showed that chromatin looping brings the master regulators adjacent to the genes that they appear to affect. The looping pattern seems to be broadly conserved among mammals. Variation in such regulatory hubs has multiple downstream effects on both genes and noncoding regions that may have shaped genome evolution and complex disease associations.
PLOS Genet. 10.1371/journal.pgen.1006673 (2017).