Project Summary Cancer epigenetics has driven a surge of research in recent years as several chromatin- associated factors have been identified in the process of tumorigenesis. A critical chromatin- modifying protein involved in active transcription, SETD2, has been found to be mutated in approximately 15% of clear cell renal cell carcinomas (ccRCCs). ccRCC patients have shown resistance to both chemotherapy and conventional radiation therapies, and although major therapeutic advances have been made, only a fraction of patients shows durable clinical responses and long-term remission; thus, there is an urgent need for novel therapies in the field. Typically, SETD2 mutations are grouped as functionally identical; however, they can be grouped according to their structural or enzymatic characteristics. This project seeks to answer the question of how the loss of SETD2 protein is molecularly distinct from loss of its enzymatic activities. The first aim will use ChIP-seq and biochemical studies to determine the relationship between SETD2 mutation and differential chromatin dysregulation and to elucidate the particular mechanism in which another protein or peptide fragment acts aberrantly in the absence of SETD2. The second aim will use ChIP-seq and cellular studies to determine how distinct molecular mechanisms of SETD2 mutations in the context of ccRCC results in differential ccRCC development and progression. The multi-disciplinary environment in the Banaszynski laboratory fosters collaboration amongst diverse scientists and trainees benefit from the guidance of Dr. Banaszynski and established scientists in the Green Center for Reproductive Biology. By the end of this training fellowship period, I will accomplish four goals, I will : 1) become a disciplined experimentalist, 2) gain ownership of my data, 3) grasp a thorough understanding of the foundational and current literature that shapes the field of cancer biology, and 4) be an effective scientific communicator and leader.