A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance
| Autor: | Agnieszka Kokot, Noah Sciaky, Jeremy M. Simon, Hyeong-Min Lee, Lorena Galiano Arjona, Nerea Ruiz Blanes, M. Bram Kuijer, Andrea Cerase, Benjamin D. Philpot, Ellen P. Clark, Sanchita Bhatnagar, Megumi Aita |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Methyl-CpG-Binding Protein 2 Janus Kinase inhibitors Neurodegenerative Congenital Mice 0302 clinical medicine Rett syndrome X Chromosome Inactivation Psychology X chromosome AG490 Pediatric 0303 health sciences Janus kinase 2 Kinase JAK-STAT signaling pathway JAK/STAT Janus Kinase MeCP2 PI3K/ATK pathways X-chromosome inactivation Animals Chromosomes Female Mutation Rett Syndrome 5.1 Pharmaceuticals Development of treatments and therapeutic interventions congenital hereditary and neonatal diseases and abnormalities Cognitive Neuroscience Biology X-inactivation stat Pathology and Forensic Medicine MECP2 lcsh:RC321-571 03 medical and health sciences Rare Diseases mental disorders Genetics lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry 030304 developmental biology Research Neurosciences Molecular biology Brain Disorders nervous system diseases Orphan Drug Pediatrics Perinatology and Child Health biology.protein Neurology (clinical) Janus kinase 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neurodevelopmental Disorders Journal of Neurodevelopmental Disorders, Vol 12, Iss 1, Pp 1-11 (2020) Journal of neurodevelopmental disorders, vol 12, iss 1 |
| Popis: | Background Rett 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. Methods Toward 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. Results We 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. Conclusions Our results suggest that inhibition of the JAK/STAT pathway is a new potential pathway to reinstate MeCP2 gene expression as an efficient RTT treatment. |
| Databáze: | OpenAIRE |
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