Screening for Noise in Gene Expression Identifies Drug Synergies

摘要

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.