Molecular mechanisms of chromatin and epigenetic regulation

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PROJECT SUMMARY The long-term goal of our research program is to define molecular mechanisms regulating chromatin modification signaling. We are particularly interested in understanding the complex relationship between DNA methylation and histone posttranslational modifications; two key epigenetic regulators of genome accessibility and function. Within this broad framework, we question 1) how are the writers and erasers of chromatin modifications regulated, 2) how do nuclear proteins and their complexes interface with (i.e., read) epigenetic marks to perform their chromatin regulatory functions, and 3) how does deregulation of chromatin signaling contribute to human disease? Our current studies are focused on UHRF1, an E3 ubiquitin ligase that is the cornerstone of a pathway responsible for maintaining a major portion of the DNA methylation found in mammalian cells. We recently showed that UHRF1 functions as a key regulator of DNA methylation inheritance through its interconnected reader and writer activities toward histone H3. While details of how UHRF1 performs its regulatory function are beginning to be uncovered, major gaps in knowledge exist in our basic molecular understanding of DNA methylation regulation and the role of UHRF1 in this process. Projects in the lab under this framework will question 1) how does UHRF1 interact with and modify chromatin, 2) what is the relationship between UHRF1, DNA methylation, and genome accessibility, 3) what is the role of histone ubiquitination in DNA methylation regulation, and 4) how does the structurally related protein UHRF2 regulate DNA methylation? Through a multidisciplinary and collaborative research program that leverages strengths in biochemical, biophysical, structural, genomic, proteomic, and cell-based studies of chromatin and epigenetic regulation, we hope to translate basic knowledge of epigenetic mechanism into therapeutic benefit.