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Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome.


ABSTRACT: Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d(+/?Geo) mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d(+/?Geo) mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome.

SUBMITTER: Bjornsson HT 

PROVIDER: S-EPMC4406328 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome.

Bjornsson Hans T HT   Benjamin Joel S JS   Zhang Li L   Weissman Jacqueline J   Gerber Elizabeth E EE   Chen Yi-Chun YC   Vaurio Rebecca G RG   Potter Michelle C MC   Hansen Kasper D KD   Dietz Harry C HC  

Science translational medicine 20141001 256


Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro  ...[more]

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