Journal
GENES & DEVELOPMENT
Volume 24, Issue 10, Pages 980-985Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1890410
Keywords
Transcription factor; protein-binding microarray; DNA-binding site affinity; eye development; mathematical modeling; gene regulation
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Funding
- Canadian Institutes of Health Research
- NIH [R01 HG003985, R01 EY10123]
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How transcription factors interpret the cis-regulatory logic encoded within enhancers to mediate quantitative changes in spatiotemporally restricted expression patterns during animal development is not well understood. Pax6 is a dosage-sensitive gene essential for eye development. Here, we identify the Prep1 (pKnox1) transcription factor as a critical dose-dependent upstream regulator of Pax6 expression during lens formation. We show that Prep1 activates the Pax6 lens enhancer by binding to two phylogenetically conserved lower-affinity DNA-binding sites. Finally, we describe a mechanism whereby Pax6 levels are determined by transcriptional synergy of Prep1 bound to the two sites, while timing of enhancer activation is determined by binding site affinity.
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