Dr. Chakraporty’s laboratory studies chromatin biology in the context of dysregulated activity of oxygen-dependent enzymes (or dioxygenase), such as the JumonjiC-family histone demethylases (or KDMs). The physiological implications of dioxygenase dysfunction is relevant in kidney cancer, where these enzymes are often mutated; and also more broadly in the context of hypoxic tumors, where these enzymes can be inactivated due to inadequate oxygen availability. The laboratory’s central theme is to exploit dioxygenase dysfunction—and the resulting epigenetic anomalies—to identify targetable vulnerabilities in the context of cancer. To address these goals, the laboratory is currently focused on three major questions: 1.) Defining the Relevance of the EZH1 histone methyltransferase as a Target in Kidney Cancer. The lab’s previous work showed that the EZH1 histone methyltransferase counteracts the deleterious effects of KDM dysfunction in kidney cancer. Using a diverse array of genetic and pharmacological tools, in combination with genomics and metabolomics analyses, the lab is now studying the mechanisms of this EZH1 dependency. In collaboration with the kidney cancer clinicians at Cleveland Clinic, the lab hopes to ultimately explore the feasibility of targeting EZH1 for kidney cancer therapy. 2.) Defining the Contribution of Dioxygenases in Cell State and Differentiation. Recently the lab described that certain KDMs, such as KDM6A, act as cellular “Oxygen Sensors”. By responding to changes in physiological oxygen, the "oxygen sensors" act as molecular switches that profoundly influence cellular response to hypoxia. The lab is now investigating the biological consequences of hypoxia-dependent inactivation of these enzymes in human cancer. By developing novel high-throughput genetic and chemical screening strategies, the laboratory hopes to define actionable therapeutic interventions that can redress the biological consequences of KDM loss in human pathologies. 3.) Exploiting Dioxygenase Dysfunction to Identify Super-enhancer Linked Genetic Dependencies. The lab previously identified specific histone modification signatures in kidney cancer [e.g. accumulation of Histone H3 modified by acetylation at Lysine 27 (H3K27ac)]. H3K27ac routinely decorates certain enhancer-dense regulatory clusters, called super-enhancers, which typically mark critical genes that regulate cellular identity and/or tumorigenic state. Consistent with this theme, the lab has identified numerous super-enhancer linked targets in kidney cancer. In ongoing work the lab is employing metabolomics analysis, genetic screens, and pharmacological tools to define super-enhancer linked dependencies in kidney cancer. In time, the lab hopes that one or more of these candidates could become prospects for therapeutic targeting.
