THE V(D)J RECOMBINATIONAL AND TRANSCRIPTIONAL ACTIVITIES OF THE IMMUNOGLOBULIN HEAVY-CHAIN INTRONIC ENHANCER CAN BE MEDIATED THROUGH DISTINCT PROTEIN-BINDING SITES IN A TRANSGENIC SUBSTRATE

Immunoglobulin and T-cell receptor gene transcriptional enhancers enco mpass sequences which stimulate V(D)J recombination of associated vari able gene segments. To address the question of whether enhancer mediat ed transcriptional activation and recombinational activation depend on the same cis-regulatory sequences, we have produced transgenic mice b y using recombination substrates containing various mutations in the i mmunoglobulin heavy-chain intronic enhancer (E mu). Analysis of substr ate rearrangements indicated that specific compound elements including E-box transcriptional motifs are crucial for the recombinational acti vity of E mu in the developing B and T lymphocytes. In most cases, a f aithful correlation between the levels of substrate germ line transcri ption and recombination was observed. However, some of the E mu mutant s which were able to activate transcription of the unrearranged Substr ate were inefficient in stimulating transgene recombination, implying that the latter function depends on molecular events other than the me re activation of transcription and that both activities can be mediate d through distinct regulatory sequences. Together, these results suppo rt a model in which lymphoid gene enhancers, in addition to providing docking sites for factors that dictate transcriptional accessibility, must have some specific function(s) for activating V(D)J recombination .