The Drosophila Dpp (BMP) signalling pathway regulates target genes through the activity of Mad (Smad) transcription factors. Smads can promote gene expression by binding to activating elements (AEs) and displacing the co-repressor Brinker (Brk), or by inhibiting expression of the brk gene. Alternatively, Smad/Schnurri co-repressor complexes can bind to silencer elements (SEs) to prevent transcription. Although the sequence-specific ability of SEs to recruit co-factors is well characterised, the sequence specificity of AEs is largely unknown. Now, George Pyrowolakis and colleagues show that the wider regulatory environment, and not the AE sequences themselves, controls transcription. Focussing on two cis-regulatory modules (CRMs) of wishful thinking (wit), a direct target of Dpp, the researchers identify the minimal enhancers driving expression in two tissues. In somatic follicle cells, relief from Brk-mediated repression drives wit expression through the witF CRM. Conversely, the CRM regulating expression in the wing imaginal disc (witW) requires alleviation of Brk and binding of Smads. Despite these different mechanisms of activation, swapping the AEs between witF and witW does not affect wit expression in either tissue. Replacing the AE sequence with an SE, however, abolishes transcriptional activity. These data show that the transcriptional response to BMP is mediated by the context of the overall enhancer and not its AE sequence.
