Suboptimization of developmental enhancers

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Science  16 Oct 2015:
Vol. 350, Issue 6258, pp. 325-328
DOI: 10.1126/science.aac6948

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For gene enhancers, less is more

Weak enhancer sequences provide just the right amount of gene activity. Farley et al. systematically examined millions of synthetic variants of the Otx enhancer, a motif needed for gene expression in the nervous system of the sea squirt Ciona. Proper gene activity resulted when there were imperfect matches to the motif showing strongest enhancer binding and gene activation. When “optimal” motifs were incorporated, ectopic expression ensued, with aberrant gene activation outside the nervous system.

Science, this issue p. 325


Transcriptional enhancers direct precise on-off patterns of gene expression during development. To explore the basis for this precision, we conducted a high-throughput analysis of the Otx-a enhancer, which mediates expression in the neural plate of Ciona embryos in response to fibroblast growth factor (FGF) signaling and a localized GATA determinant. We provide evidence that enhancer specificity depends on submaximal recognition motifs having reduced binding affinities (“suboptimization”). Native GATA and ETS (FGF) binding sites contain imperfect matches to consensus motifs. Perfect matches mediate robust but ectopic patterns of gene expression. The native sites are not arranged at optimal intervals, and subtle changes in their spacing alter enhancer activity. Multiple tiers of enhancer suboptimization produce specific, but weak, patterns of expression, and we suggest that clusters of weak enhancers, including certain “superenhancers,” circumvent this trade-off in specificity and activity.

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