Integrating sex- and tissue-specific regulation within a single Drosophila enhancer.

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Abstract
We have investigated the integration of sex- and tissue-specific transcriptional regulation in Drosophila. A single copy of the o-r enhancer from yolk protein genes directs female- and fat body-specific transcription. It consists of four protein-binding sites: dsxA, which binds male (DSXM) and female (DSXF) proteins encoded by the doublesex gene; aef1, which binds the AEF1 repressor; bzip1, which binds the DmC/EBP activator encoded by the slbo gene; and ref1, which binds an unknown activator. Multimeric and mutated binding sites were used in protein binding, germ-line transformation, and genetic experiments to examine the independent and combinatorial activities of the proteins and DNA sites. DSXF activates from dsxA by sterically excluding AEF1 repressor from the aef1 site and synergistically activating transcription together with a protein at bzip1. Sex specificity in fat bodies arises from the opposite effect of DSXM, which represses activity of the protein at bzip1. Tissue specificity is regulated by all four DNA sites. Separately, bzip1 and ref1 activate transcription in ovarian somatic cells and all nongonadal tissues, respectively, whereas together they activate only in fat bodies. The aef1 site represses ectopic transcription in ovaries and dsxA antirepresses this activity in fat bodies. Thus, in the organism, ref1 and bzip1 act combinatorially to direct the fundamental tissue specificity, aef1 and dsxA modulate this tissue specificity, and dsxA adds sex specificity.