ArticleProceedings of the National Academy of Sciences of the United States of America2016
A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
- Noncanonical role of MTP-18 in mitochondrial function and aging via electron transport chain interactions in Caenorhabditis elegans.Biogerontology · 2026Article
- Xist condensates: perspectives for therapeutic intervention.Genome biology · 2025Review
- Biodegradable magnesium based metal materials inhibit the growth of cervical cancer cells.Scientific reports · 2024Article
- The interferon γ pathway enhances pluripotency and X-chromosome reactivation in iPSC reprogramming.Science advances · 2024Article
- Multiplex epigenome editing ofScience translational medicine · 2023Article
- Selective Xi reactivation and alternative methods to restore MECP2 function in Rett syndrome.Trends in genetics : TIG · 2022Review
- A lifelong duty: how Xist maintains the inactive X chromosome.Current opinion in genetics & development · 2022Review
- The Molecular and Nuclear Dynamics of X-Chromosome Inactivation.Cold Spring Harbor perspectives in biology · 2022Review
- BAF complex-mediated chromatin relaxation is required for establishment of X chromosome inactivation.Nature communications · 2022Article
- Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells.Stem cell reports · 2022Article
- Effects of Aurora kinase A on mouse decidualization via Stat3-plk1-cdk1 pathway.Reproductive biology and endocrinology : RB&E · 2021Article
- The use of DNA methylation clock in aging research.Experimental biology and medicine (Maywood, N.J.) · 2021Review
- MeCP2: The Genetic Driver of Rett Syndrome Epigenetics.Frontiers in genetics · 2021Review
- A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance.Journal of neurodevelopmental disorders · 2020Article
- Review
- Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1.Journal of human genetics · 2019Article
- Xist RNA antagonizes the SWI/SNF chromatin remodeler BRG1 on the inactive X chromosome.Nature structural & molecular biology · 2019Article
- Tsix-Mecp2 female mouse model for Rett syndrome reveals that low-level MECP2 expression extends life and improves neuromotor function.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Pharmacological reactivation of inactive X-linkedProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Human cis-acting elements regulating escape from X-chromosome inactivation function in mouse.Human molecular genetics · 2018Article
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Authors and funding
15 authors at 8 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.