Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 50, Pages 14366-14371Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1617597113
Keywords
X reactivation; high-throughput screen; small molecules; Aurora kinase; DNA methyltransferase
Categories
Funding
- Molecular Libraries Program [1 U54 HG005032-01]
- Rett Syndrome Research Trust
- NIH [R03-MH097478, R01-DA36895]
- National Center for Research Resources Grant [1S10RR023440-01]
- Human Frontier Science Program
- Charles King Postdoctoral Fellowships
- Fund for Scientific Research-Flanders
- Belgian American Educational Foundation
- Plateforme pour l'Education et le Talent
- National Center for Advancing Translational Sciences
- Molecular Libraries Initiative of the NIH Roadmap for Medical Research [U54MH084681]
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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 similar to 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.
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