title: Screening for noise in gene expression identifies drug synergies.
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.
authors.affiliation: The Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Roy D
authors.initials: RD
authors.lastname: Dar
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Nina N
authors.initials: NN
authors.lastname: Hosmane
authors.affiliation: 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.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.affiliation: 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.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
authors.affiliation: 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.
authors.forename: Leor S
authors.initials: LS
authors.lastname: Weinberger
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D055808:Drug Discovery / Q000706:statistics & numerical data*; D004353:Drug Evaluation, Preclinical / Q000706:statistics & numerical data*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects*; D005820:Genetic Testing / Q000706:statistics & numerical data; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013269:Stochastic Processes; D014775:Virus Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D054852:Small Molecule Libraries