UC Riverside

DNA methylation plays essential roles in epigenetic regulation, development, and disease. Here, structural, biochemical, and biophysical approaches were used to investigate mechanisms underlying DNA methylation regulation in plant and mammalian systems.Structural and biochemical analyses of the plant methyltransferase DRM2 revealed that DNA conformational dynamics contribute directly to CHH substrate selectivity. Cryo-electron microscopy analyses of mammalian DNA methyltransferase DNMT3A and the leukemia-associated hotspot mutant DNMT3A R882H revealed a multi-domain autoinhibitory oligomeric architecture and a pathogenic filamentous assembly mechanism associated with dominant-negative inhibition of DNA methylation activity. Together, these studies provide mechanistic insights into how DNA conformational dynamics and higher-order methyltransferase assembly regulate epigenetic specificity in development and disease.