Screening for noise in gene expression identifies drug synergies

Roy David 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 - Jan 1 2014
Externally publishedYes

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Noise
Gene Expression
Pharmaceutical Preparations
HIV
Small Molecule Libraries
Drug Combinations
Drug Discovery

ASJC Scopus subject areas

  • General

Cite this

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

Screening for noise in gene expression identifies drug synergies. / Dar, Roy David; Hosmane, Nina N.; Arkin, Michelle R.; Siliciano, Robert F.; Weinberger, Leor S.

In: Science, Vol. 344, No. 6190, 01.01.2014, p. 1392-1396.

Research output: Contribution to journalArticle

Dar, RD, Hosmane, NN, Arkin, MR, Siliciano, RF & Weinberger, LS 2014, 'Screening for noise in gene expression identifies drug synergies', Science, vol. 344, no. 6190, pp. 1392-1396. https://doi.org/10.1126/science.1250220
Dar RD, Hosmane NN, Arkin MR, Siliciano RF, Weinberger LS. Screening for noise in gene expression identifies drug synergies. Science. 2014 Jan 1;344(6190):1392-1396. https://doi.org/10.1126/science.1250220
Dar, Roy David ; Hosmane, Nina N. ; Arkin, Michelle R. ; Siliciano, Robert F. ; Weinberger, Leor S. / Screening for noise in gene expression identifies drug synergies. In: Science. 2014 ; Vol. 344, No. 6190. pp. 1392-1396.
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