Roy Dar, Assistant Professor of Bioengineering, will lecture on “Modulating Gene Expression Fluctuations to Bias HIV Decision-Making and Stem Cell Fate Determination.” Jennifer Walters, MBM trainee and PhD student in Neuroscience, will give an introduction.
The lecture is free and open to the public at 4:00pm November 10, 2021 in 2269 Beckman Institute. The lecture is free and open to the public courtesy of the Miniature Brain Machinery Program.
Stochastic fluctuations are inherent to gene expression and can drive cell-fate specification. We exploit such fluctuations to control reactivation of human immunodeficiency virus (HIV) from latency—a quiescent state that is a major barrier to cure HIV. Using high-throughput single-cell screening, we have identified compounds that modulate HIV gene–expression fluctuations (i.e., “noise”), without changing mean expression.
These noise-modulating compounds would be neglected in conventional screens, and yet, they synergize or suppress the activity of potent activators in both Jurkat and primary cell models of viral latency. Therapies that reactivate and clear the latent reservoir are only partially effective, while latency promoting agents (LPAs) used to suppress reactivation and stabilize latency are under-studied and lack diversity in their mechanisms of action. The LPAs discovered in our noise drug screen stabilize latency and reduce latent reactivation when challenged by synergistic and potent combinations of HIV activators. These LPAs may provide new strategies to complement antiretroviral treatments.
Finally, I will discuss our recent efforts to control pluripotent gene expression noise in mouse embryonic stem cells (mESCs) with cell cycle arresting treatments. Understanding biochemical control of cell cycle and pluripotent gene expression noise can provide a foundation for designing mESC co-differentiation and multiple lineage commitment. Screening and assaying the modulation of gene expression noise presents an unexplored axis for drug discovery to control diseases and diverse cell-fate decisions.