3'-IGH ENHANCER ELEMENTS SHIFT SYNERGISTIC INTERACTIONS DURING B-CELLDEVELOPMENT

IgH gene expression is tightly controlled over the course of B cell de velopment, B cell activation, and the subsequent differentiation of th ese cells into Ig-secreting plasmacytes. There are several transcripti onal enhancers that map within and downstream of the IgH locus, and so me of these have been clearly implicated in the developmental regulati on of IgH gene assembly and expression. While some of the individual e nhancers from this locus have been studied extensively, the functional interactions possible among this group of enhancers have been largely unexplored. In the present study, we have measured the transcriptiona l activities of combinations of enhancers introduced into B-lineage ce ll lines at several different developmental stages. We detected a deve lopmental progression in which the 3' enhancers are initially inactive , then become strongly active through synergistic interactions, and fi nally achieve a strong level of activity with little interdependency. The relative contributions of E mu (the intron enhancer) and of the 3' enhancers also change as a function of developmental stage. We discus s these results in light of parallel studies of developmental changes in transcription factor requirements.