PROJECT SUMMARY/ABSTRACT An emerging hallmark of cancer is epigenetic alteration, which often results directly from somatic mutations of genes encoding chromatin factors or secondarily from hyperactive signal transduction or metabolic changes. These epigenetic changes in turn render cancer cells highly reliant on the chromatin machinery to maintain the malignant state, thus creating opportunities for therapeutic intervention by targeting chromatin. Histone post- translational modifications (PTMs) carry an epigenetic layer of message that can be recognized and decoded by dedicated protein “readers” to regulate fundamental DNA-templated processes. Therefore, these recognition events constitute key mechanisms underlying transcriptional control in cancer. We recently discovered that ENL, a YEATS domain-containing protein, acts as a novel reader for histone acetylation to regulate oncogenic gene expression and is essential for the maintenance of a wide range of aggressive leukemia. Structural study revealed an acetyl-lysine binding pocket in the ENL YEATS domain that is amenable for drug targeting. Furthermore, recurrent mutations in the ENL YEATS domain were recently reported in Wilms tumor, the most common kidney tumor in children and associated with poor outcome, indicating a broad and important role of ENL in cancer. The goal of this project is to fully elucidate the mechanisms by which ENL and its tumor- associated mutations establish and/or maintain the malignant state in cancer. During the mentored phase of the award, the PI will apply innovative approaches to identify the combinatory histone codes and DNA-binding factors that determine the gene-specific targeting of ENL (Aim 1). The PI will also identify and characterize effector proteins that mediate the gene regulatory function of ENL in leukemia (Aim 2). During the independent phase, the PI proposes to study the roles of tumor-associated ENL YEATS mutations by testing the hypothesis that the mutations confer gain of function in chromatin targeting and transcriptional control to drive the development of Wilms tumors (Aim 3). Together, results from these studies will provide novel insights into epigenetic reader- mediated processes in cancer and advance the exploration of new therapeutic avenues for the associated cancer. Under the guidance of an exceptional team of mentors, the PI will acquire new training in chromatin chemical biology, computational epigenomics, and transcription regulation, which will critically contribute to the PI’s career development and put her in a unique position to apply integrated approaches to reveal new insights into the epigenetic control in cancer. The Rockefeller University and its neighboring institutions provide an outstanding environment for the PI to carry out the...