FMR1 ENHANCER IS REGULATED BY CAMP THROUGH A CAMP-RESPONSIVE ELEMENT

FMR1 (Fra X Mental Retardation 1), a gene of unknown function, is resp onsible for an important hereditary mental retardation, the fragile X syndrome. In this study, a 22-bp enhancer (methylation sensitive eleme nt, MSE) in the FMR1 promoter was defined by DNase I footprinting assa y, and the binding of this element by nuclear factor was prevented by DNA CpG methylation. A cAMP-responsive element (CRE)-like sequence and a myc-binding sequence in MSE were identified. In the transfection as say, MSE demonstrated a strong, methylation-sensitive enhancer activit y. MSE could be bound by recombinant CRE-binding protein (CREB), and i ts activity was stimulated by CREB in a co-transfection assay. In PC12 cells, forskolin elevated MSE activity several fold, and this inducti on was abolished in CRE mutants. The involvement of cAMP in the expres sion of FMR1 should be a clue to both the function of FMR1 and the pat hogenesis of fragile X syndrome.