Publication Date:
2014-06-07
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122234/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122234/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dar, Roy D -- Hosmane, Nina N -- Arkin, Michelle R -- Siliciano, Robert F -- Weinberger, Leor S -- AI104380/AI/NIAID NIH HHS/ -- DP2 OD006677/OD/NIH HHS/ -- DP2-OD006677/OD/NIH HHS/ -- F32 AI104380/AI/NIAID NIH HHS/ -- P30AI027763/AI/NIAID NIH HHS/ -- P50GM081879/GM/NIGMS NIH HHS/ -- T32 GM008752/GM/NIGMS NIH HHS/ -- U19 AI096113/AI/NIAID NIH HHS/ -- U19AI096113/AI/NIAID NIH HHS/ -- UL1 TR001079/TR/NCATS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 20;344(6190):1392-6. doi: 10.1126/science.1250220. Epub 2014 Jun 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158, USA. ; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ; 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. ; 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. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24903562" target="_blank"〉PubMed〈/a〉
Keywords:
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/genetics/physiology
;
Humans
;
Promoter Regions, Genetic/drug effects
;
Small Molecule Libraries/*pharmacology
;
Stochastic Processes
;
Virus Activation/drug effects/genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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