We investigate how the epigenome influences genomes and tissues, and how epigenetic regulation contributes to both disease and normal physiology. To this end, we develop cutting-edge tools that enable us to broadly explore fundamental organizational principles of biological systems. These include epigenetic MERFISH, which provides subcellular-resolution epigenomic profiling, and CRISPR-based screens to pinpoint the regulators of tissue organization and the 3D epigenome.