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- Title
A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance.
- Authors
Lee, Hyeong-Min; Kuijer, M. Bram; Ruiz Blanes, Nerea; Clark, Ellen P.; Aita, Megumi; Galiano Arjona, Lorena; Kokot, Agnieszka; Sciaky, Noah; Simon, Jeremy M.; Bhatnagar, Sanchita; Philpot, Benjamin D.; Cerase, Andrea
- Abstract
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.
- Publication
Journal of Neurodevelopmental Disorders, 2020, Vol 12, Issue 1, pN.PAG
- ISSN
1866-1947
- Publication type
Article
- DOI
10.1186/s11689-020-09332-3