ArticleJournal of neurodevelopmental disorders2020
A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance.
Article in Journal of neurodevelopmental disorders, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- From inactivation to intervention: X chromosome silencing in disease pathogenesis and emerging therapeutic strategies.Genes & diseases · 2026Review
- From Gene to Hope: Rett Syndrome and the Rise of Molecular Therapies.Molecular diagnosis & therapy · 2026Review
- Lyonization of X-chromosome: New insights.Journal of genetics · 2026Review
- Xist condensates: perspectives for therapeutic intervention.Genome biology · 2025Review
- Exploring the complexity of MECP2 function in Rett syndrome.Nature reviews. Neuroscience · 2025Review
- FERM domain-containing proteins are active components of the cell nucleus.Life science alliance · 2024Review
- Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities.Journal of neurodevelopmental disorders · 2024Review
- Genomic analysis in Chilean patients with suspected Rett syndrome: keep a broad differential diagnosis.Frontiers in genetics · 2024Article
- Rett Syndrome: A Tale of Altered Genetics, Synaptic Plasticity, and Neurodevelopmental Dynamics.Cureus · 2023Review
- State-of-the-art therapies for Rett syndrome.Developmental medicine and child neurology · 2023Review
- Multiplex epigenome editing ofScience translational medicine · 2023Article
- Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives.Frontiers in neuroscience · 2023Review
- Neuroprotective Properties of Cardoon Leaves Extracts against Neurodevelopmental Deficits in an In Vitro Model of Rett Syndrome Depend on the Extraction Method and Harvest Time.Molecules (Basel, Switzerland) · 2022Article
- Selective Xi reactivation and alternative methods to restore MECP2 function in Rett syndrome.Trends in genetics : TIG · 2022Review
- Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity.Cell death discovery · 2022Article
- The Molecular and Nuclear Dynamics of X-Chromosome Inactivation.Cold Spring Harbor perspectives in biology · 2022Review
- Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells.Stem cell reports · 2022Article
- Review
- Disease-modifying therapies for Rett syndrome: a review for neurologists.Frontiers in neurologyReview
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundRett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. While MeCP2 mutations are lethal in most males, females survive birth but show severe neurological defects. Because X-chromosome inactivation (XCI) is a random process, approximately 50% of the cells silence the wild-type (WT) copy of the MeCP2 gene. Thus, reactivating the silent WT copy of MeCP2 could provide therapeutic intervention for RTT.
methodsToward this goal, we screened ~ 28,000 small-molecule compounds from several libraries using a MeCP2-luciferase reporter cell line and cortical neurons from a MeCP2-EGFP mouse model. We used gain/increase of luminescence or fluorescence as a readout of MeCP2 reactivation and tested the efficacy of these drugs under different drug regimens, conditions, and cellular contexts.
resultsWe identified inhibitors of the JAK/STAT pathway as XCI-reactivating agents, both by in vitro and ex vivo assays. In particular, we show that AG-490, a Janus Kinase 2 (JAK2) kinase inhibitor, and Jaki, a pan JAK/STAT inhibitor, are capable of reactivating MeCP2 from the inactive X chromosome, in different cellular contexts.
conclusionsOur results suggest that inhibition of the JAK/STAT pathway is a new potential pathway to reinstate MeCP2 gene expression as an efficient RTT treatment.
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