Recapitulation and reversal of schizophrenia-related phenotypes in <i>Setd1a</i>-deficient mice

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<jats:title>Summary</jats:title><jats:p><jats:italic>SETD1A</jats:italic>, a histone methyltransferase, is a key schizophrenia susceptibility gene. Mutant mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics, accompanied by specific deficits in working memory that recapitulates SCZ-related alterations. We show that Setd1a targets mostly enhancers and reveal a striking overlap between Setd1a and Mef2 chromatin targets. Setd1a targets are highly expressed in pyramidal neurons and enriched for genes with postnatally-biased expression involved in synaptic structure and function. Notably, evolutionary conserved Setd1a binding sites and target genes are strongly associated with neuropsychiatric genetic risk burden. Reinstating <jats:italic>Setd1a</jats:italic> expression in adulthood rescues working memory deficits. We identify LSD1 as a major demethylase counteracting the effects of Setd1a methyl transferase activity and show that LSD1 antagonism in adult <jats:italic>Setd1a</jats:italic>-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how <jats:italic>SETD1A</jats:italic> mutations predispose to SCZ and point to therapeutic interventions.</jats:p>

収録刊行物

  • Neuron

    Neuron 104 (3), 471-487.e12, 2019-01-26

    Cold Spring Harbor Laboratory

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