We are developing quantitative experimental strategies to dissect the fundamental principles of gene regulation. Our approach combines large-scale manipulation of the regulatory system using high–throughput genome engineering with the implementation of quantitative multi-dimensional readouts to determine the effects of the generated perturbations. To test the contribution of genetic information in the establishment of epigenetic states, we developed an experimental strategy to insert several hundred DNA sequence variants in parallel into the same genomic locus and to determine their DNA methylation status. The comprehensive dataset generated by this approach revealed the importance of transcription factors in controlling the epigenetic state of regulatory regions (Krebs et al., eLife, 2014). Most methods currently used in genomics rely on averaging signal over large populations of cells. To overcome this limitation, we recently developed Single Molecule Footprinting (SMF); a methodology to quantify protein-DNA contacts at the level of single DNA molecules in vivo. Applying this technique genome-wide enabled us to dissect the complex sequence of binding events that lead to transcription initiation (Krebs et al., Mol Cell, 2017). Future projects and goals The group will develop and apply novel experimental and computational strategies for genomics. We will attempt to improve the resolution of current genomics assays towards the measure of regulatory events at the level of single cells and single DNA molecules. We will devise methodologies to perform large-scale genetic manipulations to dissect the function of regulatory DNA. Additionally, we will implement strategies to promote the use of advanced genomics techniques to study complex multi-cellular systems through close collaborations with fellow groups at EMBL. We will combine these advances to address several fundamental questions such as: How is genetic information translated into gene expression patterns? What is the functional impact of epigenetic modifications on the function of regulatory regions?