Lecturer: Dr. Roy Dar
Affilliation: University of California, San Francisco
Abstract:
Stochastic fluctuations are inherent to gene
expression and can drive cell-fate specification.
We used such fluctuations to modulate reactivation
of HIV from latency—a quiescent state that is
a major barrier to an HIV cure.
By screening a diverse library of bioactive small
molecules, we identified over 80 compounds
that modulated HIV gene-expression fluctuations
(i.e. ‘noise’), without changing mean expression.
These noise-modulating compounds would be
neglected in conventional screens and strikingly
they synergized with conventional transcriptional
activators. Noise enhancers reactivated latent cells
significantly better than existing best-in-class
reactivation cocktails (and with reduced off-target
cytotoxicity), while noise suppressors stabilized
latency. Noise-modulating chemicals may provide
novel probes for the physiological consequences
of noise and an unexplored axis for drug discovery,
allowing enhanced control over diverse cell-fate
decisions.