Kabuki syndrome: Reversing Intellectual Disability by Promoting Open Chromatin
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Date
2015-11-16
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Johns Hopkins University
Abstract
Kabuki syndrome (KS) is a rare intellectual disability syndrome caused by mutations in two genes (KMT2D and KDM6A) both involved in promoting open chromatin. If an imbalance between open and closed chromatin states is central to the pathogenesis of KS, we hypothesized that agents that promote chromatin opening might have therapeutic potential. To test this hypothesis, we have characterized a novel mouse model of KS with a heterozygous deletion in the mouse Kmt2d gene (Kmt2d+/βGeo), leading to the impairment of methyltransferase function. Novel in vitro reporter alleles demonstrate a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d+/βGeo mice, which responds to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell (DG GCL) layer of Kmt2d+/βGeo mice correlates with reduced neurogenesis and volume as well as hippocampal memory defects. These abnormalities improve upon postnatal treatment with two weeks of AR-42. Additionally we report that treatment with a ketogenic diet elevates beta-hydroxybutyrate (BHB), an endogenous HDACi. Ketogenic diet treatment is also able to modulate H3Ac and H3K4me3 in the DG GCL, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice. We were also observed similar effects in the rescue of neurogenesis upon exogenous administration of BHB. Furthermore, Kmt2d+/βGeo mice appear to have a NADH/NAD+ ratio abnormality that predisposes them to have increased elevation of BHB on a ketogenic diet, suggesting that this dietary treatment may be especially productive for specific syndrome. Overall, our work suggests that a reversible deficiency of postnatal neurogenesis underlies intellectual disability in KS, and that both pharmacological and dietary agents that promote open chromatin appear to be viable strategies for potential treatment strategy for the intellectual disability seen in Kabuki syndrome and related disorders.
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Keywords
Kabuki syndrome, HDACi, epigenetics, Mll2, Kmt2d