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

Journal of Neurodevelopmental Disorders

Nerea Ruiz Blanes¹  Lorena Galiano Arjona¹  Andrea Cerase¹  Agnieszka Kokot²  Sanchita Bhatnagar²  M. Bram Kuijer³  Ellen P. Clark³  Megumi Aita³  Benjamin D. Philpot⁴  Hyeong-Min Lee⁵  Noah Sciaky⁶  Jeremy M. Simon⁷ 

[1] Blizard Institute, Queen Mary University of London, London, UK;Department of Biochemistry and Molecular Genetics, Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, USA;Department of Cell Biology & Physiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA;Department of Cell Biology & Physiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA;UNC Neuroscience Center, Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, USA;Department of Cell Biology & Physiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA;UNC Neuroscience Center, Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, USA;Current Address: High-Throughput Bioscience Center, Chemical Biology & Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA;Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA;UNC Neuroscience Center, Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, USA;Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA;

关键词: Rett syndrome;    MeCP2;    X-chromosome inactivation;    AG490;    Janus Kinase;    Janus Kinase inhibitors;    JAK/STAT;    PI3K/ATK pathways;   

DOI  :  10.1186/s11689-020-09332-3

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY