A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance
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(2020) 12:29
RESEARCH
Open Access
A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance Hyeong-Min Lee1,2,3, M. Bram Kuijer1, Nerea Ruiz Blanes4, Ellen P. Clark1, Megumi Aita1, Lorena Galiano Arjona4, Agnieszka Kokot5, Noah Sciaky6, Jeremy M. Simon2,7, Sanchita Bhatnagar5, Benjamin D. Philpot1,2 and Andrea Cerase4*
Abstract Background: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methylCpG 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. Keywords: Rett syndrome, MeCP2, X-chromosome inactivation, AG490, Janus Kinase, Janus Kinase inhibitors, JAK/ STAT, PI3K/ATK pathways
Introduction Rett syndrome (RTT) is a severe neurodevelopmental disorder often classified as an autism spectrum disorder (ASD). About 90% of reported cases of individuals with RTT inherit de novo mutations of the methyl-CpGbinding protein 2 (MeCP2) gene [1]. The detailed mechanism of how MeCP2 mutations lead to RTT is largely unknown; however, mutations in MeCP2 are associated * Correspondence: [email protected] 4 Blizard Institute, Queen Mary University of London, London, UK Full list of author information is available at the end of the article
with defects in neuronal development and synapse formation [2, 3]. A deficiency of MeCP2 leads to immature synaptic development in the cortex [4–6] and disruption of the metabolism of brain cholesterol, resulting in abnormal neuronal function [7, 8]. Mutations affecting the nuclear localization signal region of MeCP2 or early truncating mutations are responsible for a severe phenotype in comparison to missense mutations, whereas C-terminal mutations are associated with milder phenotypes [9, 10]. As MeCP2 is also expressed in glia,
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attrib
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