Decoding the transcriptional program of epidermal cell morphogenesis. Francois Payre^1,2, Delphine Menoret^1,2, Marc Santolini³, Isabelle Fernandes^1,2, Jennifer Zanet^1,2, Yvan Latapie^1,2, Pierre Ferrer^1,2, Herve Rouault³, Vincent Hakim³, Philippe Besse⁴, Ignacio Gonzales⁴, Rebecca Spokony⁵, Keven White⁵, Stein Aerts⁶, Serge Plaza^1,2. 1) Centre for Developmental Biology, University of Toulouse, Toulouse, France; 2) CNRS, UMR5547, Toulouse, France; 3) Laboratoire de Physique Statistique, ENS, Paris, France; 4) Institut de Mathematique, Toulouse, France; 5) Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, USA; 6) Laboratory of Computational Biology, KU Leuven, Belgium.

   Developmental programs are implemented by regulatory interactions between Transcription Factors (TFs) and their target genes. How the Cis-Regulatory-Modules (CRMs) mediating these interactions are built and function during terminal differentiation remains yet poorly understood. We addressed this question in late Drosophila embryogenesis when the finely tuned expression of a Transcription Factor, Ovo/Shavenbaby (Svb), triggers the morphological differentiation of epidermal trichomes. Here we find that Svb regulates a large set of terminal effectors of trichome formation, as deduced from microarray profiling and experimental validation. Combining genome-wide approaches, computational modelling and in vivo functional dissection, we investigated the nature and logic of CRMs directing the expression of Svb-dependent effectors. We find that Svb-responsive CRMs display weak if any clustering of Svb binding sites. In addition, the in vivo function of each site relies on its intimate context, with a critical importance of adjacent nucleotides. Finally, Svb-responsive CRMs display various combinations of additional cis-regulatory elements, which contribute to different levels of activity. Together, these results show that trichome formation is underpinned by an unexpectedly flexible mode of regulation, shedding novel light on the functional organization of CRMs mediating terminal differentiation.