PROJECT SUMMARY/ ABSTRACT Recent landmark discoveries have revealed that in addition to DNA lesions, epigenetic mechanisms also play a major role in cancer. Epigenetics is mediated in part by interactions of proteins and DNA that confer heritable gene expression states. Drugging the cancer epigenome is a burgeoning medical technology that currently uses small molecule inhibitors and small RNAs to disrupt hyperactive epigenetic enzymes. The proposed work will test the hypothesis that a new modality, fusion proteins that interact with the chromatin fiber, will activate therapeutic genes at sites that bear a specific pattern of cancer-related biochemical marks. The specific aims are to (2) use bioinformatic analyses to discover chromosome features that support inducible changes in gene expression states and (2) to use protein engineering to identify determinants of nuclear protein engagement.