Intrinsic promoter responsiveness dictates sensitivity to transcriptional activation by enhancers

Recent studies have developed various reporter assays to test many enhancer and promoter sequences in combination, but arrived at different conclusions and have not yet provided quantitative measurements that predict the effects of enhancers in their endogenous locations in the genome.

To resolve this, we systematically compare 6 different reporter assay designs, and identify and resolve critical confounders in measuring enhancer-promoter compatibility. With redesigned reporter assays, we show that enhancers are broadly compatible with promoters, but promoters show large differences in responsiveness to enhancers (e.g. 40-fold versus <2-fold activation by a strong enhancer).