Complex Control of the Immunoglobulin Heavy-Chain Gene 
enhancer-binding protein, ZEB, may solve that 
problem; we are exploring the possibility that 
ZEB is the repressor. It binds the same region of 
the enhancer that is bound by E2-5 but does not 
bind some of the other sites (found in other 
genes) that are bound by E2-5. Moreover, not all 
sites bound by ZEB will bind E2-5. This overlap- 
ping, yet distinct, binding specificity should al- 
low us to evaluate whether ZEB (or something 
like ZEB) is the repressor. 
We have demonstrated that one component of 
the heavy-chain enhancer's cell-type specificity 
results from a balance between positive- and nega- 
tive-acting transcription factors. In Drosophila, 
such protein gradients are thought to establish 
transcriptional repertoires that dictate pat- 
tern formation during embryonic development. 
Hence, although our findings contradict the 
model initially proposed that only lymphoid 
cells possess the appropriate positive-acting fac- 
tors, they are not without precedent. In fact, it 
appears that the enhancer uses both types of 
mechanisms to mediate lymphoid specificity. 
The protein Oct- 2 activates the enhancer 
(through its binding site) and is found only in 
lymphoid cells. Moreover, we have recently iso- 
lated the gene for an additional B cell-restricted 
enhancer-binding protein. Experiments are 
under way to evaluate this protein's role in en- 
hancer activity. 
Although we are just beginning to scratch the 
surface in our understanding of transcriptional 
control, the immunoglobulin heavy-chain en- 
hancer has served as an important paradigm by 
reflecting its potential complexity. It is likely 
that many other genes employ such protein gra- 
dients, perhaps combined with cell type- 
specific factors, to mediate their transcriptional 
activities. It is now thought that a group of pro- 
teins, all highly related to E2-5 (encoded by the 
same gene) , activates transcription of not just im- 
munoglobulin genes in B cells but of muscle- 
specific and pancrease-specific genes as well. 
These very different rolesfor E2-5 may reflect its 
ability to form heterodimers with a variety of 
other proteins of similar type but with distinct 
modes of expression. This combinatorial control 
undoubtedly serves to increase the overall variety 
of transcriptional repertoires available to the 
multitude of cell types within an organism. 
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