Neuron
Volume 104, Issue 3, 6 November 2019, Pages 471-487.e12
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Article
Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice

https://doi.org/10.1016/j.neuron.2019.09.014Get rights and content
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Highlights

  • Cognitive and circuitry deficits in a mouse model of SETD1A, a schizophrenia risk gene

  • Reinstating Setd1a or antagonizing LSD1 activity in adulthood rescues deficits

  • Setd1a binds promoters and enhancers with a striking overlap with Mef2 on enhancers

  • Evolutionarily conserved Setd1a-bound enhancers may regulate psychiatric risk genes

Summary

SETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional up- and downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions.

Keywords

SETD1A
MEF2
LSD1
histone methyltransferase
enhancer
loss-of-function mutation
schizophrenia
axonal branching
working memory
pharmacological reversal

Cited by (0)

7

These authors contributed equally

8

Present address: Laboratory of Molecular Psychiatry and Neuroscience, Research and Development Center for Precision Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8550, Japan

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Present address: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China

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