Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (MEF2C) motif enrichment in sequences surrounding the top scoring single-nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base-pair resolution in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within cis-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term Mef2c upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging in vivo by Mef2c-Dam adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders.
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KJB is a New York Stem Cell Foundation—Robertson Investigator. The Brennand Laboratory is supported by a Brain and Behavior Young Investigator Grant, National Institute of Health (NIH) grants R01 MH101454 and R01 MH106056, and the New York Stem Cell Foundation. ACM was supported by a Young Investigator Award of the Brain Behavior Research Foundation, and NIH grant R01 MH106056 and P50 MH096890 (SA). We thank the Harvard Brain Tissue Resource Center, the Maryland Psychiatric Research Center, and Dr WE Bunney Jr and Dr EG Jones (deceased) from the University of California, Irvine and University of California, Davis, for providing postmortem tissue samples for ChIP-seq and chromosome conformation capture. As per our agreement with Coriell Cell Repository, some human induced pluripotent stem cell lines generated from control and SZ fibroblasts will be available from Coriell. In addition, all Coriell collection control and SZ human induced pluripotent stem cells have been deposited with the NIMH Center for Collaborative Studies of Mental Disorders at RUCDR. RNA-seq data provided by the CommonMind Consortium were supported by funding from Takeda Pharmaceuticals Company Limited, F Hoffman-La Roche Ltd and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the CommonMind Consortium is from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Mitchell, A., Javidfar, B., Pothula, V. et al. MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice. Mol Psychiatry 23, 123–132 (2018). https://doi.org/10.1038/mp.2016.254
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