Screening for noise in gene expression identifies drug synergies

Roy D. Dar, Nina N. Hosmane, Michelle R. Arkin, Robert F. Siliciano, Leor S. Weinberger

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)1392-1396
Number of pages5
JournalScience
Volume344
Issue number6190
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • General

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    Dar, R. D., Hosmane, N. N., Arkin, M. R., Siliciano, R. F., & Weinberger, L. S. (2014). Screening for noise in gene expression identifies drug synergies. Science, 344(6190), 1392-1396. https://doi.org/10.1126/science.1250220