Here you will find brief descriptions of the projects that currently take up my time and occupy my attention. If you have any questions, thoughts, comments or feedback, please get in touch!
Biological roles of cytoplasmic RNA-protein aggregates.
Plasticity of gene expression programs allows cells to respond and adapt to stress. This adaptive ability is not only critical to maximize survival of normal cells in response to stresses but is also required for both the initial cancerous transformation as well as tumor response to anticancer therapies. Translational regulation is particularly crucial in situations that demand a rapid response. Cellular stresses such as starvation, oxidative stress, heat shock or viral infections induce an Integrated Stress Response (ISR) involving global translation reduction and sequestering mRNA into stress granules (SGs); dynamic, non-membrane bound, phase-separated cytoplasmic organelles. However, adaptive responses to insults require increased translation of a diverse set of stress-responsive genes, which must occur selectively even under a reduced overall translation paradigm. The mechanisms by which this selective translation is achieved under stress remain incompletely understood.
Many RNA binding proteins aggregate in SGs, and granule dynamics are important in determining how cells respond to adverse environmental conditions to maximize survival. Although historically studied as a singular entity, granules within a cell are diverse and heterogenous in terms of their RNA and protein composition.
I am using a combination of molecular and cellular methods to investigate the contributions of granule heterogeneity in maximizing cellular survival and fitness, as well as to elucidate the mechanisms by which these granules contribute to gene regulation under stress.
Remodeling of RNA by DEAD-box RNA chaperones
Cellular protein levels often show poor correlation with transcript levels, indicating at significant translational control. Most of this control is regulated via sequences contained in 5′ or 3′ untranslated regions (UTR), surrounding the mRNA coding sequence (CDS). Past research in the lab has shown that the DEAD-box RNA chaperone DDX3 selectively controls translation of a subset of mRNAs. Variants in DDX3X are a previously unappreciated yet common cause of global developmental delay in humans.
Using a combination of genome engineering and biochemical efforts, I am looking to investigate the transcript space whose translation is influenced by DDX3X.