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

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dc.contributor Landspitali - The National University Hospital of Iceland
dc.contributor.author Zhang, Li
dc.contributor.author Pilarowski, Genay
dc.contributor.author Pich, Emilio Merlo
dc.contributor.author Nakatani, Atsushi
dc.contributor.author Dunlop, John
dc.contributor.author Baba, Rina
dc.contributor.author Matsuda, Satoru
dc.contributor.author Daini, Masaki
dc.contributor.author Hattori, Yasushi
dc.contributor.author Matsumoto, Shigemitsu
dc.contributor.author Ito, Mitsuhiro
dc.contributor.author Kimura, Haruhide
dc.contributor.author Björnsson, Hans Tómas
dc.date.accessioned 2022-06-01T01:02:37Z
dc.date.available 2022-06-01T01:02:37Z
dc.date.issued 2021-03-12
dc.identifier.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
dc.identifier.issn 2329-0501
dc.identifier.other PURE: 43006805
dc.identifier.other PURE UUID: 67b9e308-73a1-4d14-8649-7b807717050a
dc.identifier.other Scopus: 85102008056
dc.identifier.uri https://hdl.handle.net/20.500.11815/3211
dc.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)
dc.description.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.
dc.format.extent 13
dc.format.extent 779-791
dc.language.iso en
dc.relation.ispartofseries Molecular Therapy - Methods and Clinical Development; 20()
dc.rights info:eu-repo/semantics/openAccess
dc.subject Sameindalíffræði
dc.subject Kabuki heilkenni
dc.subject Kabuki heilkenni
dc.subject adult neurogenesis
dc.subject chromatin
dc.subject epigenetics
dc.subject ERK
dc.subject H3K4me1
dc.subject H3K4me3
dc.subject histone modification
dc.subject LSD1
dc.subject splenomegaly
dc.subject therapeutics
dc.subject Molecular Medicine
dc.subject Molecular Biology
dc.subject Genetics
dc.title Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome
dc.type /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article
dc.description.version Peer reviewed
dc.identifier.pmid 33738331
dc.identifier.doi https://doi.org/10.1016/j.omtm.2021.02.011
dc.relation.url http://www.scopus.com/inward/record.url?scp=85102008056&partnerID=8YFLogxK
dc.contributor.department Faculty of Medicine
dc.contributor.department Clinical Laboratory Services, Diagnostics and Blood Bank

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