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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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s11689-020-09332-3.

A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance