MODULATION OF THE IGH ENHANCERS CELL TYPE SPECIFICITY THROUGH A GENETIC SWITCH

Using defined regions of the immunoglobulin heavy-chain enhancer linked to minimal promoters and cDNAs that encode the two helix-loop-helix transcription factors ITF-1 and TFE3, we demonstrate that activity of an otherwise repressed enhancer can be stimulated in nonlymphoid cells. Repression in non-B cells is mediated by the mu-E5 motif. Derepression occurs at two levels. First, overexpression of ITF-1, an E12/E47-related protein that binds the mu-E5 motif, leads to transcriptional activation itself. Second, binding of ITF-1 physically displaces a repressor that normally blocks the stimulatory activity of TFE3, which binds the neighboring mu-E3 motif. TFE3 can only stimulate enhancer activity in the presence of ITF-1 or in the absence of a mu-E5 motif. Hence, one component of the enhancer's cell type specificity can be artificially modulated through a "genetic switch" in which activity is dictated by the relative levels of ITF-1 and a competing repressor.