title: Rapid evolutionary rewiring of a structurally constrained eye enhancer.
abstract: BACKGROUND
  Enhancers are genomic cis-regulatory sequences that integrate spatiotemporal signals to control gene expression. Enhancer activity depends on the combination of bound transcription factors as well as-in some cases-the arrangement and spacing of binding sites for these factors. Here, we examine evolutionary changes to the sequence and structure of sparkling, a Notch/EGFR/Runx-regulated enhancer that activates the dPax2 gene in cone cells of the developing Drosophila eye.
  
  
  RESULTS
  Despite functional and structural constraints on its sequence, sparkling has undergone major reorganization in its recent evolutionary history. Our data suggest that the relative strengths of the various regulatory inputs into sparkling change rapidly over evolutionary time, such that reduced input from some factors is compensated by increased input from different regulators. These gains and losses are at least partly responsible for the changes in enhancer structure that we observe. Furthermore, stereotypical spatial relationships between certain binding sites ("grammar elements") can be identified in all sparkling orthologs-although the sites themselves are often recently derived. We also find that low binding affinity for the Notch-regulated transcription factor Su(H), a conserved property of sparkling, is required to prevent ectopic responses to Notch in noncone cells.
  
  
  CONCLUSIONS
  Rapid DNA sequence turnover does not imply either the absence of critical cis-regulatory information or the absence of structural rules. Our findings demonstrate that even a severely constrained cis-regulatory sequence can be significantly rewired over a short evolutionary timescale.
authors: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors: Christina I
authors: CI
authors: Swanson
authors: David B
authors: DB
authors: Schwimmer
authors: Scott
authors: S
authors: Barolo
mesh_terms: D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D005123:Eye / Q000254:growth & development / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018010:Receptors, Invertebrate Peptide / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005136:Eye Proteins; C497759:N protein, Drosophila; D018010:Receptors, Invertebrate Peptide; D051880:Receptors, Notch; C107990:sv protein, Drosophila; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors