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

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.

• Authors: 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
• Journal: Molecular therapy. Methods & clinical development (Mol Ther Methods Clin Dev) Vol. 20 Pg. 779-791 (Mar 12 2021) ISSN: 2329-0501 [Print] United States
• PMID: 33738331 (Publication Type: Journal Article)
• Copyright: © 2021 The Author(s).