Significance: The genetic code of the DNA provides a universal building plan for the cell’s molecular machinery. But a second code is needed to control the complexity of the human body, organizing 100 billion cells with identical genomes into 200 specialized cell types. This second code is called “epigenetic”. Defects in the epigenetic code play an important role in cancer, and they create an opportunity for new therapies. The proposed project is based on the hypothesis that dynamic and non-random changes of the epigenome contribute to cancer progression. I will quantitatively reconstruct the epigenome dynamics observed in leukemia and infer drug combinations that can reprogram the cancer epigenome to a less malignant stage.Innovation & Approach: Technological breakthroughs have created an exciting opportunity for biomedical research: It is now possible to measure the full spectrum of epigenetic regulation operating on top of the genome and to comprehensively characterize the effect of epigenetic interventions. Capitalizing on recent advances, I will pursue an ambitious research agenda on epigenomics in biomedicine that can be summarized by the following formula: (Cancer Epigenetics + Biomedical Sequencing + Computational Modeling) • X = Biomedical Discovery.The proposed project will cohesively combine basic biology with high-throughput technology and cutting-edge bioinformatics. The multiplying factor X denotes seamless integration – rather than addition – of all three components with equal importance and dedication, giving rise to a systems-level approach to studying epigenomics in biomedicine. The following three specific aims will be pursued:Aim 1. Establish an epigenome research platform addressing biomedical questions (technology development)Aim 2. Dissect the epigenome dynamics of leukemia progression (disease mechanisms & diagnostics)Aim 3. Rational design of epigenetic combination therapies for cancer (drug effects & genomic medicine)