TitleSuboptimization of developmental enhancers.
Publication TypeJournal Article
Year of Publication2015
AuthorsFarley, EK, Olson, KM, Zhang, W, Brandt, AJ, Rokhsar, DS, Levine, MS
JournalScience
Volume350
Issue6258
Pagination325-8
Date Published2015 Oct 16
KeywordsAnimals, Base Sequence, Binding Sites, Ciona intestinalis, Consensus Sequence, Enhancer Elements, Genetic, Fas-Associated Death Domain Protein, Fibroblast Growth Factors, GATA Transcription Factors, Gene Expression Regulation, Developmental, Molecular Sequence Data, Organ Specificity, Otx Transcription Factors
Abstract

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.

Alternate JournalScience