Enhancer cooperativity can compensate for loss of activity over large genomic distances

Enhancers are short DNA sequences that regulate target gene from a distance and in spatio-temporal patterns. The expression of many genes is controlled by combinations of multiple enhancers, but the interaction and cooperation of individual enhancer elements is not well understood. We developed a novel synthetic platform that allows building complex regulatory landscape from the bottom up. We tested the system by integrating individual enhancers at different distances and confirmed that with increasing distance to the promoter, expression of the reporter gene decreased. However, the reduction level depends on the enhancer’s intrinsic strength. Furthermore, introducing a weak enhancer between a strong enhancer and the promoter can partially rescue the decreased reporter gene expression. Therefore, synergy between enhancer elements can increase the genomic distance from which enhancers can function.