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

Screening for noise in gene expression identifies drug synergies.

Author information

1
The Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158, USA.
2
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Small Molecule Discovery Center, University of California, San Francisco, Mission Bay Campus, CA 94158, USA.Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94143, USA. leor.weinberger@gladstone.ucsf.edu.
4
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Howard Hughes Medical Institute, Baltimore, MD 21205, USA. leor.weinberger@gladstone.ucsf.edu.
5
The Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158, USA.QB3: California Institute for Quantitative Biosciences, University of California, San Francisco, CA 94158, USA.Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA. leor.weinberger@gladstone.ucsf.edu.

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.

PMID:
24903562
PMCID:
PMC4122234
DOI:
10.1126/science.1250220
[Indexed for MEDLINE]
Free PMC Article

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