دورية أكاديمية
Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome
| العنوان: | Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome |
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| المؤلفون: | Zhang, Li, Pilarowski, Genay, Pich, Emilio Merlo, Nakatani, Atsushi, Dunlop, John, Baba, Rina, Matsuda, Satoru, Daini, Masaki, Hattori, Yasushi, Matsumoto, Shigemitsu, Ito, Mitsuhiro, Kimura, Haruhide, Björnsson, Hans Tómas |
| المساهمون: | Faculty of Medicine, Clinical Laboratory Services, Diagnostics and Blood Bank, Landspitali - The National University Hospital of Iceland |
| سنة النشر: | 2021 |
| المجموعة: | Opin vísindi (Iceland) |
| مصطلحات موضوعية: | Sameindalíffræði, Kabuki heilkenni, adult neurogenesis, chromatin, epigenetics, ERK, H3K4me1, H3K4me3, histone modification, LSD1, splenomegaly, therapeutics, Molecular Medicine, Molecular Biology, Genetics |
| الوصف: | 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) ; 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | 779-791 |
| اللغة: | English |
| تدمد: | 2329-0501 |
| العلاقة: | Molecular Therapy - Methods and Clinical Development; 20(); http://www.scopus.com/inward/record.url?scp=85102008056&partnerID=8YFLogxKTest; 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.2021.02.011Test; 67b9e308-73a1-4d14-8649-7b807717050a; 85102008056; https://hdl.handle.net/20.500.11815/3211Test |
| DOI: | 10.1016/j.omtm.2021.02.011 |
| الإتاحة: | https://doi.org/20.500.11815/3211Test https://doi.org/10.1016/j.omtm.2021.02.011Test https://hdl.handle.net/20.500.11815/3211Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.838E1CAF |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 23290501 |
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| DOI: | 10.1016/j.omtm.2021.02.011 |