A. Bailly et al., An enhancer element 6 kb upstream of the mouse HNF4 alpha 1 promoter is activated by glucocorticoids and liver-enriched transcription factors, NUCL ACID R, 29(17), 2001, pp. 3495-3505
We have characterized a 700 bp enhancer element around -6 kb relative to th
e HNF4 alpha1 transcription start. This element increases activity and conf
ers glucocorticoid induction to a heterologous as well as the homologous pr
omoters in differentiated hepatoma cells and is transactivated by HNF4 alph
a1, HNF4 alpha7, HNF1 alpha and HNF1 beta in dedifferentiated hepatoma cell
s. A 240 bp sub-region conserves basal and hormone-induced enhancer activit
y. It contains HNF1, HNF4, HNF3 and C/EBP binding sites as shown by DNase I
footprinting and electrophoretic mobility shift assays using nuclear extra
cts and/or recombinant HNF1 alpha and HNF4 alpha1. Mutation analyses showed
that the HNF1 site is essential for HNF1 alpha transactivation and is requ
ired for full basal enhancer activity, as is the C/EBP site. Glucocorticoid
response element consensus sites which overlap the C/EBP, HNF4 and HNF3 si
tes are crucial for optimal hormonal induction. We present a model that acc
ounts for weak expression of HNF4 alpha1 in the embryonic liver and strong
expression in the newborn/adult liver via the binding sites identified in t
he enhancer.