2024-2029 R01 (NINDS): Regulation of phase separation in neuronal heterochromatin

The primary objective of this project is to determine how the formation of heterochromatin is driven by targets of the degradative ubiquitin ligase anaphase-promoting complex (APC), including Ki-67 and phosphorylated histone 3. The elegant experiments we propose aim to test the hypothesis that these APC-targets drive heterochromatin formation by promoting the biophysical process of phase separation. Achieving these aims will provide fundamental insight into the role of chromatin regulation in neurons and the contribution of this process to inherited disorders of neurodevelopment. 

2024-2026 R21 (NINDS): Recognition and ubiquitination of neurodevelopmental chromatin regulators

The objectives of this project are to deepen our understanding of the molecular functions of the ubiquitin ligase Anaphase-Promoting Complex (APC) in inherited neurodevelopmental disorders. We previously identified key mechanisms by which APC-mediated ubiquitin signaling controls the composition of heterochromatin in neurons, and we are proposing sophisticated structural experiments to understand how ubiquitin ligases recognize substrates within protein complexes. These experiments will provide crucial molecular insight that hastens progress toward modulating key ubiquitin signaling pathways and/or their targets in order to therapeutically intervene in the pathogenesis of a class of debilitating diseases that represent a major unmet medical need. 

2019-2024 K08 (NICHD): Ubiquitin signaling in epigenetic regulation of neuronal development

This project seeks to understand the molecular and cellular pathogenesis of a novel form of inherited neurodevelopmental disorder due to mutation in a major ubiquitin signaling pathway. In the process of characterizing the mutant mouse model we developed to study the affected patients, we have identified epigenetic alterations during brain development. The experiments I have proposed will advance our understanding of the molecular pathways that underlie chromatin maturation in neurons, which would be harnessed for therapy in neurodevelopmental disorders.