title: Suboptimization of developmental enhancers.
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.
authors.affiliation: Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. msl2@princeton.edu ekfarley@princeton.edu.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Farley
authors.affiliation: Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Olson
authors.affiliation: Department of Medicine, University of California, San Diego, CA 92093-0688, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of California, Berkeley, CA 94720-3200, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Brandt
authors.affiliation: Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Rokhsar
authors.affiliation: Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. msl2@princeton.edu ekfarley@princeton.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002938:Ciona intestinalis / Q000235:genetics / Q000254:growth & development*; D016384:Consensus Sequence; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D050980:GATA Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics / Q000502:physiology; D051857:Otx Transcription Factors / Q000378:metabolism*
chemical_list: D053200:Fas-Associated Death Domain Protein; D050980:GATA Transcription Factors; D051857:Otx Transcription Factors; D005346:Fibroblast Growth Factors