Screening for noise in gene expression identifies drug synergies

Science. 2014 Jun 20;344(6190):1392-6. doi: 10.1126/science.1250220. Epub 2014 Jun 5.


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 more than 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 yet, they synergized with conventional transcriptional activators. Noise enhancers reactivated latent cells significantly better than existing best-in-class reactivation drug combinations (and with reduced off-target cytotoxicity), whereas 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Drug Discovery / statistics & numerical data*
  • Drug Evaluation, Preclinical / statistics & numerical data*
  • Drug Synergism
  • Gene Expression / drug effects*
  • Genetic Testing / statistics & numerical data
  • HIV / drug effects*
  • HIV / genetics
  • HIV / physiology
  • Humans
  • Promoter Regions, Genetic / drug effects
  • Small Molecule Libraries / pharmacology*
  • Stochastic Processes
  • Virus Activation / drug effects
  • Virus Activation / genetics


  • Anti-HIV Agents
  • Small Molecule Libraries