NSF Award
1715892
Epigenetics is a layer of information that exists on top of the regular genome to regulate the expression of genes; the molecules that orchestrate this information can contribute to human health and disease. Two epigenetic molecules, called UHRF1 and UHRF2, have distinct cellular functions, but are not well characterized at the molecular level. The proposed research seeks to determine the molecular differences by which UHRF1 and UHRF2 interact with epigenetic material. The project will establish a productive and collaborative research program that provides valuable scientific training for ~12-14 undergraduate students at Eastern Michigan University (EMU). Strong mentorship and cross-disciplinary training will provide students with critical thinking and research skills so they are prepared to succeed in future biomedical careers. The research plan will also be integrated into undergraduate biochemistry lab courses to give additional students the learning benefits of research. Together, the proposed work will strengthen the academic and research environment at EMU and increase basic knowledge in the area of epigenetics. <br/><br/>Histone reader proteins engage epigenetic modifications and play a central role in the regulation of many nuclear processes such as transcription, DNA replication and DNA repair. The detailed molecular mechanisms by which many of these proteins mediate histone recognition remain unknown; thus this represents a major gap in our current understanding of how these proteins impart specificity and regulate the epigenetic apparatus. This research focuses on the histone reader protein UHRF2, a close homolog of UHRF1 with distinct nuclear functions. While UHRF1-histone interactions are well studied, very little is known on the molecular and structural requirements of histone recognition by UHRF2. The goal of this project is to determine the molecular and structural mechanisms by which the histone binding domains of UHRF2 functionally interact with histone H3. Equilibrium binding assays, mutagenesis and crystallographic approaches will be utilized to elucidate the mechanisms that dictate histone-binding specificity between UHRF1 and UHRF2. This research will provide molecular insights as to how histone reader proteins distinguish and engage their cognate PTMs and advance fundamental understanding of epigenetic regulation.
