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Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome

Li Zhang, Genay Pilarowski, Emilio Merlo Pich, Atsushi Nakatani, John Dunlop, Rina Baba, Satoru Matsuda, Masaki Daini, Yasushi Hattori, Shigemitsu Matsumoto, Mitsuhiro Ito, Haruhide Kimura, View ORCID ProfileHans Tomas Bjornsson
doi: https://doi.org/10.1101/2020.03.11.986976
Li Zhang
1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Genay Pilarowski
1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Emilio Merlo Pich
2Takeda Pharmaceutical Company Limited. Fujisawa, Kanagawa, Japan
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Atsushi Nakatani
2Takeda Pharmaceutical Company Limited. Fujisawa, Kanagawa, Japan
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John Dunlop
3Takeda Pharmaceutical Company Limited, London, United Kingdom
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Rina Baba
2Takeda Pharmaceutical Company Limited. Fujisawa, Kanagawa, Japan
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Satoru Matsuda
2Takeda Pharmaceutical Company Limited. Fujisawa, Kanagawa, Japan
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Masaki Daini
2Takeda Pharmaceutical Company Limited. Fujisawa, Kanagawa, Japan
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Yasushi Hattori
2Takeda Pharmaceutical Company Limited. Fujisawa, Kanagawa, Japan
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Shigemitsu Matsumoto
2Takeda Pharmaceutical Company Limited. Fujisawa, Kanagawa, Japan
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Mitsuhiro Ito
2Takeda Pharmaceutical Company Limited. Fujisawa, Kanagawa, Japan
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Haruhide Kimura
2Takeda Pharmaceutical Company Limited. Fujisawa, Kanagawa, Japan
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Hans Tomas Bjornsson
1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
4Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
5Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik 101, Iceland
6Landspitali University Hospital, Reykjavik, 101, Iceland
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  • ORCID record for Hans Tomas Bjornsson
  • For correspondence: hbjorns1@jhmi.edu
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Abstract

Kabuki syndrome (KS) is a rare cause of intellectual disability primarily caused by loss of function mutations in lysine-specific methyltransferase 2D (KMT2D), which normally adds methyl marks to lysine 4 on histone 3. Previous studies have shown that a mouse model of KS (Kmt2d+/βGeo) demonstrates disruption of adult neurogenesis and hippocampal memory. Proof-of-principle studies have shown postnatal rescue of neurological dysfunction following treatments that promote chromatin opening, however, these strategies are non-specific and do not directly address the primary defect of histone methylation. Since lysine-specific demethylase 1A (LSD1/KDM1A) normally removes the H3K4 methyl marks added by KMT2D, we hypothesize that inhibition of KDM1A demethylase activity may ameliorate molecular and phenotypic defects stemming from KMT2D loss. To test this hypothesis, we evaluated a recently developed KDM1A inhibitor (TAK-418) in Kmt2d+/βGeo mice. We find that orally administered TAK-418 increases the numbers of newly born Doublecortin (DCX)+ cells and processes in hippocampus in a dose dependent manner. We also observe TAK-418-dependent rescue of histone modification defects in hippocampus both by Western blot and ChIP-Seq. Treatment rescues gene expression abnormalities including those of immediate early genes such as FBJ osteosarcoma oncogene (Fos) and FBJ osteosarcoma oncogene homolog B (Fosb). After 2 weeks of TAK-418, Kmt2d+/βGeo mice demonstrate normalization of hippocampal memory defects. In summary, our data suggest that KDM1A inhibition is a plausible treatment strategy for KS and support the hypothesis that the epigenetic dysregulation secondary to KMT2D dysfunction plays a major role in the postnatal neurological disease phenotype in KS.

  • Epigenetics
  • adult neurogenesis
  • histone modification
  • therapeutics

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE146729

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome
Li Zhang, Genay Pilarowski, Emilio Merlo Pich, Atsushi Nakatani, John Dunlop, Rina Baba, Satoru Matsuda, Masaki Daini, Yasushi Hattori, Shigemitsu Matsumoto, Mitsuhiro Ito, Haruhide Kimura, Hans Tomas Bjornsson
bioRxiv 2020.03.11.986976; doi: https://doi.org/10.1101/2020.03.11.986976
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Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome
Li Zhang, Genay Pilarowski, Emilio Merlo Pich, Atsushi Nakatani, John Dunlop, Rina Baba, Satoru Matsuda, Masaki Daini, Yasushi Hattori, Shigemitsu Matsumoto, Mitsuhiro Ito, Haruhide Kimura, Hans Tomas Bjornsson
bioRxiv 2020.03.11.986976; doi: https://doi.org/10.1101/2020.03.11.986976

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