A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation
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Lessing-2016-A high-throughput small molecule.pdf
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Checksum (MD5)
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Author(s)
Lessing, Derek
Dial, Thomas O.
Wei, Chunyao
Payer, Bernhard
Carrette, Lieselot L. G.
Kesner, Barry
Szanto, Attila
Jadhav, Ajit
Maloney, David J.
Simeonov, Anton
Date Issued
November 2016
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Lessing, Derek et al. “A High-Throughput Small Molecule Screen Identifies Synergism Between DNA Methylation and Aurora Kinase Pathways for X Reactivation.” Proceedings of the National Academy of Sciences 113, 50 (December 2016): 14366–14371 © 2016 National Academy of Sciences
Version
Final published version
Abstract
X-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of >1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened ∼367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by “priming” cells with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi.
MIT Department
Broad Institute of MIT and Harvard
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1073/pnas.1617597113
