The aim of this grant is to understand the relationships between genomic topology and the control of transcription, using the HoxD locus as a paradigm. We will take a system approach in the mouse, combining tools of genetics, evolutionary genomics and biochemistry to try and model various modes of large-scale gene regulations occurring during development. The results will tell us about the mechanistic bases of global gene regulation and how such regulations evolved, by integrating these mechanisms into the evolutionnary contexts of the respective structures. The approach will make use of our unique collection of mutants at this locus along with both transcript profiling and quantitation, ChIP of several proteins (modifications thereof-) indicative of chromatin states, chromosome conformation capture (4C) and transgenesis after phylogenetic footprint. To keep datasets within reasonable scales and allow for their integration into a single model structures, we will focus on a 2 Mb large DNA interval centered around the HoxD locus, which contains range of conserved non-coding DNA sequences and includes a gene-rich island, flanked by two large gene-deserts bordered again by gene-rich regions. We will conduct systematic analyses of these multiple parameters in various embryonic tissues, at different times where and when Hox genes are required. The massive datasets generated (ca 15 different points for transcript quantification, profiling, chromatin modifications, 4C, from ca 10 different tissues at 3 developmental times, from as many as 20 mutant strains) will feed mechanistic models accounting for the modalities of these regulations. Models will be compared to one another to try and reconstitute the evolution of these regulations. Such a combination of genetics, biochemistry and modeling, carried out on a locus where global gene function is already well worked out, will give us a comprehensive view of the underlying regulatory mechanisms, with a high heuristic value