TY - JOUR
T1 - The co-activator p300 associates physically with and can mediate the action of the distal enhancer of the FGF-4 gene
AU - Nowling, Tamara
AU - Bernadt, Cory
AU - Johnson, Lance
AU - Desler, Michelle
AU - Rizzino, Angie
PY - 2003/4/18
Y1 - 2003/4/18
N2 - Distal enhancers commonly regulate gene expression. However, the mechanisms of transcriptional mediation by distal enhancers remain largely unknown. To better understand distal enhancer-mediated transcription, we examined the regulation of the FGF-4 gene. The FGF-4 gene is regulated during early development by a powerful distal enhancer located downstream of the promoter in exon 3. Sox-2 and Oct-3 bind to the enhancer and are required for the activation of the FGF-4 gene. Previously, we implicated the co-activator p300 as a mediator of Sox-2/Oct-3 synergistic activation of a heterologous promoter, suggesting that p300 may play a role in mediating enhancer activation of the FGF-4 gene. In this study, we provide both functional and physical evidence that p300 plays an important role in the action of the FGF-4 enhancer. Specifically, we show that E1a, but not a mutant form of E1a that is unable to bind p300, inhibits enhancer activation of the FGF-4 promoter. We also demonstrate that Gal4/p300 fusion proteins can stimulate the FGF-4 promoter when bound to the FGF-4 enhancer. Additionally, we present evidence that p300 mediation of the FGF-4 enhancer requires acetyltransferase activity. Importantly, we also show that Sox-2 and p300 are physically associated with the endogenous FGF-4 enhancer but weakly associated with the endogenous FGF-4 promoter. These results are consistent with a model of transitory interaction between the distal enhancer and the FGF-4 promoter. Our results also suggest that intragenic distal enhancers may use mechanisms that differ from extragenic distal enhancers.
AB - Distal enhancers commonly regulate gene expression. However, the mechanisms of transcriptional mediation by distal enhancers remain largely unknown. To better understand distal enhancer-mediated transcription, we examined the regulation of the FGF-4 gene. The FGF-4 gene is regulated during early development by a powerful distal enhancer located downstream of the promoter in exon 3. Sox-2 and Oct-3 bind to the enhancer and are required for the activation of the FGF-4 gene. Previously, we implicated the co-activator p300 as a mediator of Sox-2/Oct-3 synergistic activation of a heterologous promoter, suggesting that p300 may play a role in mediating enhancer activation of the FGF-4 gene. In this study, we provide both functional and physical evidence that p300 plays an important role in the action of the FGF-4 enhancer. Specifically, we show that E1a, but not a mutant form of E1a that is unable to bind p300, inhibits enhancer activation of the FGF-4 promoter. We also demonstrate that Gal4/p300 fusion proteins can stimulate the FGF-4 promoter when bound to the FGF-4 enhancer. Additionally, we present evidence that p300 mediation of the FGF-4 enhancer requires acetyltransferase activity. Importantly, we also show that Sox-2 and p300 are physically associated with the endogenous FGF-4 enhancer but weakly associated with the endogenous FGF-4 promoter. These results are consistent with a model of transitory interaction between the distal enhancer and the FGF-4 promoter. Our results also suggest that intragenic distal enhancers may use mechanisms that differ from extragenic distal enhancers.
UR - http://www.scopus.com/inward/record.url?scp=0038529806&partnerID=8YFLogxK
U2 - 10.1074/jbc.M207567200
DO - 10.1074/jbc.M207567200
M3 - Article
C2 - 12488456
AN - SCOPUS:0038529806
SN - 0021-9258
VL - 278
SP - 13696
EP - 13705
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 16
ER -