Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome

Summary

Gene expression is in part controlled by cis-regulatory elements (CREs) such as enhancers and repressive elements. Anecdotal evidence has indicated that a CRE and a promoter need to be biochemically compatible for promoter regulation to occur, but this compatibility has remained poorly characterized in mammalian cells. We used high-throughput combinatorial reporter assays to test thousands of CRE-promoter pairs from three Mb-sized genomic regions in mouse cells. This revealed that CREs vary substantially in their promoter compatibility, ranging from striking specificity to broad promiscuity. More than half of the tested CREs exhibit significant promoter selectivity. Housekeeping promoters tend to have similar CRE preferences, but other promoters exhibit a wide diversity of compatibilities. Higher-order transcription factors (TF) motif combinations may account for compatibility. CRE-promoter selectivity does not correlate with looping interactions in the native genomic context, suggesting that chromatin folding and compatibility are two orthogonal mechanisms that confer specificity to gene regulation.

Graphical abstract

Highlights

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  Intrinsic compatibility of thousands of enhancer-promoter combinations was tested

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  Compatibilities exhibit a broad spectrum, from promiscuous to highly specific

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  Enhancer-promoter compatibility and chromatin looping appear to be independent

Abstract

A major question in genome biology is how enhancers “choose” their target promoter. Using high-throughput reporter assays, Martinez-Ara and colleagues surveyed the intrinsic compatibilities of thousands of enhancer-promoter pairs in mouse cells. They found a wide diversity of specificities, mostly likely driven by a complex grammar of sequence motifs.