Precise temporal control of the eye regulatory gene Pax6 via enhancer-binding site affinity.
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.
Rowan
Sheldon
S
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Siggers
Trevor
T
Lachke
Salil A
SA
Yue
Yingzi
Y
Bulyk
Martha L
ML
Maas
Richard L
RL
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005136:Eye Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism*; D007908:Lens, Crystalline / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D013997:Time Factors
D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; C491412:Pknox1 protein, mouse; D012097:Repressor Proteins