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

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


Title: Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome
Author: Zhang, Li
Pilarowski, Genay
Pich, Emilio Merlo
Nakatani, Atsushi
Dunlop, John
Baba, Rina
Matsuda, Satoru
Daini, Masaki
Hattori, Yasushi
Matsumoto, Shigemitsu
... 3 more authors Show all authors
Date: 2021-03-12
Language: English
Scope: 13
University/Institute: Landspitali - The National University Hospital of Iceland
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: Molecular Therapy - Methods and Clinical Development; 20()
ISSN: 2329-0501
DOI: https://doi.org/10.1016/j.omtm.2021.02.011
Subject: Sameindalíffræði; Kabuki heilkenni; Kabuki heilkenni; adult neurogenesis; chromatin; epigenetics; ERK; H3K4me1; H3K4me3; histone modification; LSD1; splenomegaly; therapeutics; Molecular Medicine; Molecular Biology; Genetics
URI: https://hdl.handle.net/20.500.11815/3211

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Citation:

Zhang , L , Pilarowski , G , Pich , E M , Nakatani , A , Dunlop , J , Baba , R , Matsuda , S , Daini , M , Hattori , Y , Matsumoto , S , Ito , M , Kimura , H & Björnsson , H T 2021 , ' Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome ' , Molecular Therapy - Methods and Clinical Development , vol. 20 , pp. 779-791 . https://doi.org/10.1016/j.omtm.2021.02.011

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 hypothesized 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 found that orally administered TAK-418 increases the numbers of newly born doublecortin (DCX) + cells and processes in the hippocampus in a dose-dependent manner. We also observed TAK-418-dependent rescue of histone modification defects in hippocampus both by western blot and chromatin immunoprecipitation sequencing (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 demonstrated 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.

Description:

Funding text 1 We are thankful for statistical analysis by Dr. Liliana Florea and Corina Antonescu, through the Computational Biology Consulting Core, and support by Dr. Pletnikov in the JHMI behavioral core. H.T.B. is funded by the following sources: NIH ( DP5OD017877 ), USA, the Louma G. Foundation , USA the Walter Zaitzeff Fund , USA the Icelandic Research Fund ( 195835-051 and 206806-051 ), Iceland and, for this project, with a grant from Takeda Pharmaceutical Company, Japan. Funding text 2 This work was partially supported with a grant from Takeda Pharmaceutical Company, who owns rights to TAK-418. E.M.P., J.D., A.N., R.B., S.M., M.D., Y.H., S.M., M.I., and H.K. are employees of Takeda Pharmaceutical Company. Publisher Copyright: © 2021 The Author(s)

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