REGULATORY GENOMICS · Regulatory Genomics in Drosophila

A major goal of biology is to explain how gene regulatory information is encoded by the genome. To date, we cannot decipher this regulatory code, despite the cells ability to read it in natural and artificial sequence contexts, and in contrast to our detailed understanding of the genetic code, which allows us to seamlessly translate DNA into protein sequences. Here, I propose a regulatory genomics approach in Drosophila with three specific objectives: First, we will determine the sequence basis of how individual Hox transcription factors (Scr, Antp, Ubx, abd-A, Abd-B) and factors downstream of signalling pathways (Sd, pan, ci, Su(H), pnt, Stat93E, Mad, Smox, CrebA) regulate different genes in different tissues. We will perform tissue-specific ChIP-Seq and measure gene expression in mesoderm/muscle, epidermis, and neurons, and explain common and tissue-specific targets by their sequences. Second, we will determine requirements for enhancer function in several different cell-types, by performing an exhaustive and unbiased enhancer screen and computationally analyzing the sequences. Third, we will build a computational model to extract general rules from objectives 1 & 2, learn the regulatory codes, and make specific predictions. We will validate our model using cross-validation and predictions with unrelated sequence (e.g. from yeast), and will finally use it to design enhancers that are active in specific cell-types or combinations of cell-types. Our combination of experimental and computational methods makes us confident that we will make major contributions to the understanding of gene regulation in the fly. We anticipate that we will learn general principles, which will hold across tissues and animals, and might ultimately lead to the general regulatory code.