Functional cooperativity between protein molecules bound at two distinct sequence elements of the immunoglobulin heavy-chain promoter

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Abstract
Immunoglobulin heavy-chain gene promoters contain two conserved upstream sequence elements, octamer and heptamer1–4, both of which are required for normal cell type-specific promoter function in vivo4–6. The octamer sequence motif 5′-ATGCAAAT-3′, and its precise inverse, are strongly conserved in heavy- and light-chain gene promoters1,2 and are important determinants for the lymphoid-specific function of these promoters7–9 and of the heavy-chain enhancer10,11. The heptameric sequence element with the consensus 5′-CTCATGA-3′ (refs 3 and 4) is also required in addition to the octamer for full lymphoid-specific activity of heavy-chain promoters4,6. Although these two elements have no sequence similarity, they are both recognized in vitro12 by the ubiquitous octamer transcription factor OTF-1 (reviewed in refs 13 and 14) and the lymphoid-specific OTF-2 (reviewed in refs 15 and 16). Here we show that purified OTF-2 binds cooperatively to the immunoglobulin heptamer and octamer elements so that interaction with the octamer element facilitates binding of OTF-2 to the heptamer motif. More important, cooperativity in OTF-2 binding is closely mirrored by functional cooperation between the heptamer and octamer elements in activating transcription from the heavy-chain promoter in vitro.