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MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice

Abstract

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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References

  1. Arion D, Corradi JP, Tang S, Datta D, Boothe F, He A et al. Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder. Mol Psychiatry 2015; 20: 1397–1405.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhao Z, Xu J, Chen J, Kim S, Reimers M, Bacanu SA et al. Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder. Mol Psychiatry 2015; 20: 563–572.

    CAS  PubMed  Google Scholar 

  3. Horvath S, Mirnics K . Schizophrenia as a disorder of molecular pathways. Biol Psychiatry 2015; 77: 22–28.

    CAS  PubMed  Google Scholar 

  4. Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P . Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci 2002; 22: 2718–2729.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Vawter MP, Shannon Weickert C, Ferran E, Matsumoto M, Overman K, Hyde TM et al. Gene expression of metabolic enzymes and a protease inhibitor in the prefrontal cortex are decreased in schizophrenia. Neurochem Res 2004; 29: 1245–1255.

    CAS  PubMed  Google Scholar 

  6. Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P . Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 2000; 28: 53–67.

    CAS  PubMed  Google Scholar 

  7. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.

    CAS  PubMed  Google Scholar 

  8. Ibrahim HM, Tamminga CA . Treating impaired cognition in schizophrenia. Curr Pharm Biotechnol 2012; 13: 1587–1594.

    CAS  PubMed  Google Scholar 

  9. Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421–427.

    Google Scholar 

  10. Colantuoni C, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 2011; 478: 519–523.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lewis DA, Sweet RA . Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. J Clin Invest 2009; 119: 706–716.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B . JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res 2004; 32: D91–D94.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Weinberger DR, Levitt P . Neurodevelopmental Origins of Schizophrenia. In: Weinberger DR, Harrison P (eds). Schizophrenia, 3rd edn. Wiley-Blackwell: Hoboken, Oxford, Singapore, 2011, pp 393–412.

    Google Scholar 

  14. Kouzarides T . Chromatin modifications and their function. Cell 2007; 128: 693–705.

    CAS  PubMed  Google Scholar 

  15. Eissenberg JC, Shilatifard A . Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev Biol 2010; 339: 240–249.

    CAS  PubMed  Google Scholar 

  16. Liu L, Jin G, Zhou X . Modeling the relationship of epigenetic modifications to transcription factor binding. Nucleic Acids Res 2015; 43: 3873–3885.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kano S, Colantuoni C, Han F, Zhou Z, Yuan Q, Wilson A et al. Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia. Mol Psychiatry 2013; 18: 740–742.

    CAS  PubMed  Google Scholar 

  18. Cheung I, Shulha HP, Jiang Y, Matevossian A, Wang J, Weng Z et al. Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proc Natl Acad Sci USA 2010; 107: 8824–8829.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Jiang Y, Matevossian A, Huang HS, Straubhaar J, Akbarian S . Isolation of neuronal chromatin from brain tissue. BMC Neurosci 2008; 9: 42.

    PubMed  PubMed Central  Google Scholar 

  20. Bonn S, Zinzen RP, Perez-Gonzalez A, Riddell A, Gavin AC, Furlong EE . Cell type-specific chromatin immunoprecipitation from multicellular complex samples using BiTS-ChIP. Nat Protoc 2012; 7: 978–994.

    CAS  PubMed  Google Scholar 

  21. Halder R, Hennion M, Vidal RO, Shomroni O, Rahman RU, Rajput A et al. DNA methylation changes in plasticity genes accompany the formation and maintenance of memory. Nat Neurosci 2016; 19: 102–110.

    CAS  PubMed  Google Scholar 

  22. Labonte B, Suderman M, Maussion G, Lopez JP, Navarro-Sanchez L, Yerko V et al. Genome-wide methylation changes in the brains of suicide completers. Am J Psychiatry 2013; 170: 511–520.

    PubMed  Google Scholar 

  23. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 2010; 38: 576–589.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang J, Duncan D, Shi Z, Zhang B . WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res 2013; 41: W77–W83.

    PubMed  PubMed Central  Google Scholar 

  25. Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 2008; 82: 696–711.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Jaffe AE, Gao Y, Deep-Soboslay A, Tao R, Hyde TM, Weinberger DR et al. Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. Nat Neurosci 2016; 19: 40–47.

    CAS  PubMed  Google Scholar 

  27. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V, Sigova AA et al. Super-enhancers in the control of cell identity and disease. Cell 2013; 155: 934–947.

    CAS  PubMed  Google Scholar 

  28. Thomas-Chollier M, Herrmann C, Defrance M, Sand O, Thieffry D, van Helden J . RSAT peak-motifs: motif analysis in full-size ChIP-seq datasets. Nucleic acids research 2012; 40: e31.

    CAS  PubMed  Google Scholar 

  29. Goujon M, McWilliam H, Li W, Valentin F, Squizzato S, Paern J et al. A new bioinformatics analysis tools framework at EMBL-EBI. Nucleic Acids Res 2010; 38: W695–W699.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 2011; 7: 539.

    PubMed  PubMed Central  Google Scholar 

  31. Shulha HP, Cheung I, Guo Y, Akbarian S, Weng Z . Coordinated cell type-specific epigenetic remodeling in prefrontal cortex begins before birth and continues into early adulthood. PLoS Genet 2013; 9: e1003433.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Aguilar-Valles A, Vaissiere T, Griggs EM, Mikaelsson MA, Takacs IF, Young EJ et al. Methamphetamine-associated memory is regulated by a writer and an eraser of permissive histone methylation. Biol Psychiatry 2014; 76: 57–65.

    CAS  PubMed  Google Scholar 

  33. Gupta S, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD et al. Histone methylation regulates memory formation. J Neurosci 2010; 30: 3589–3599.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kerimoglu C, Agis-Balboa RC, Kranz A, Stilling R, Bahari-Javan S, Benito-Garagorri E et al. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci 2013; 33: 3452–3464.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bai G, Cheung I, Shulha HP, Coelho JE, Li P, Dong X et al. Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains. Hum Mol Genet 2015; 24: 1441–1456.

    PubMed  Google Scholar 

  36. Shulha HP, Cheung I, Whittle C, Wang J, Virgil D, Lin CL et al. Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. Arch Gen Psychiatry 2012; 69: 314–324.

    CAS  PubMed  Google Scholar 

  37. Dong X, Tsuji J, Labadorf A, Roussos P, Chen JF, Myers RH et al. The Role of H3K4me3 in transcriptional regulation is altered in Huntington's disease. PLoS One 2015; 10: e0144398.

    PubMed  PubMed Central  Google Scholar 

  38. Hoftman GD, Datta D, Lewis DA . Layer 3 excitatory and inhibitory circuitry in the prefrontal cortex: developmental trajectories and alterations in schizophrenia. Biol Psychiatry 2016; S0006-3223: 32427–1.

    Google Scholar 

  39. Arnsten AF, Girgis RR, Gray DL, Mailman RB . Novel dopamine therapeutics for cognitive deficits in schizophrenia. Biol Psychiatry 2016; 81: 67–77.

    PubMed  PubMed Central  Google Scholar 

  40. Pergola G, Suchan B . Associative learning beyond the medial temporal lobe: many actors on the memory stage. Front Behav Neurosci 2013; 7: 162.

    PubMed  PubMed Central  Google Scholar 

  41. Kim J, Delcasso S, Lee I . Neural correlates of object-in-place learning in hippocampus and prefrontal cortex. J Neurosci 2011; 31: 16991–17006.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Weible AP, Rowland DC, Pang R, Kentros C . Neural correlates of novel object and novel location recognition behavior in the mouse anterior cingulate cortex. J Neurophysiol 2009; 102: 2055–2068.

    PubMed  Google Scholar 

  43. Akirav I, Maroun M . Ventromedial prefrontal cortex is obligatory for consolidation and reconsolidation of object recognition memory. Cereb Cortex 2006; 16: 1759–1765.

    PubMed  Google Scholar 

  44. Horiguchi M, Hannaway KE, Adelekun AE, Jayathilake K, Meltzer HY . Prevention of the phencyclidine-induced impairment in novel object recognition in female rats by co-administration of lurasidone or tandospirone, a 5-HT(1 A) partial agonist. Neuropsychopharmacology 2012; 37: 2175–2183.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Barbosa AC, Kim MS, Ertunc M, Adachi M, Nelson ED, McAnally J et al. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc Natl Acad Sci USA 2008; 105: 9391–9396.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Chakravarthy S, Keck T, Roelandse M, Hartman R, Jeromin A, Perry S et al. Cre-dependent expression of multiple transgenes in isolated neurons of the adult forebrain. PLoS One 2008; 3: e3059.

    PubMed  PubMed Central  Google Scholar 

  47. Rodriguez A, Ehlenberger DB, Dickstein DL, Hof PR, Wearne SL . Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS One 2008; 3: e1997.

    PubMed  PubMed Central  Google Scholar 

  48. Neve RL, Neve KA, Nestler EJ, Carlezon WA Jr. . Use of herpes virus amplicon vectors to study brain disorders. BioTechniques 2005; 39: 381–391.

    CAS  PubMed  Google Scholar 

  49. Neve RL . Overview of gene delivery into cells using HSV-1-based vectors. Curr Protoc Neurosci 2012; 61: 4.12:4.12.1–4.12.7.

    Google Scholar 

  50. Huang S, O'Donovan KJ, Turner EE, Zhong J, Ginty DD . Extrinsic and intrinsic signals converge on the Runx1/CBFbeta transcription factor for nonpeptidergic nociceptor maturation. Elife 2015; 4: e10874.

    PubMed  PubMed Central  Google Scholar 

  51. Bondi C, Matthews M, Moghaddam B . Glutamatergic animal models of schizophrenia. Curr Pharm Des 2012; 18: 1593–1604.

    CAS  PubMed  Google Scholar 

  52. Javitt DC, Zukin SR, Heresco-Levy U, Umbricht D . Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull 2012; 38: 958–966.

    PubMed  PubMed Central  Google Scholar 

  53. Anticevic A, Corlett PR, Cole MW, Savic A, Gancsos M, Tang Y et al. N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia. Biol Psychiatry 2015; 77: 569–580.

    CAS  PubMed  Google Scholar 

  54. Manahan-Vaughan D, von Haebler D, Winter C, Juckel G, Heinemann U . A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats. Hippocampus 2008; 18: 125–134.

    CAS  PubMed  Google Scholar 

  55. Shimbo T, Du Y, Grimm SA, Dhasarathy A, Mav D, Shah RR et al. MBD3 localizes at promoters, gene bodies and enhancers of active genes. PLoS Genet 2013; 9: e1004028.

    PubMed  PubMed Central  Google Scholar 

  56. Koziol MJ, Bradshaw CR, Allen GE, Costa AS, Frezza C, Gurdon JB . Identification of methylated deoxyadenosines in vertebrates reveals diversity in DNA modifications. Nat Struct Mol Biol 2016; 23: 24–30.

    CAS  PubMed  Google Scholar 

  57. van Steensel B, Delrow J, Henikoff S . Chromatin profiling using targeted DNA adenine methyltransferase. Nat Genet 2001; 27: 304–308.

    CAS  PubMed  Google Scholar 

  58. Bharadwaj R, Jiang Y, Mao W, Jakovcevski M, Dincer A, Krueger W et al. Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia. J Neurosci 2013; 33: 11839–11851.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Bharadwaj R, Peter CJ, Jiang Y, Roussos P, Vogel-Ciernia A, Shen EY et al. Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition. Neuron 2014; 84: 997–1008.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Shulha HP, Crisci JL, Reshetov D, Tushir JS, Cheung I, Bharadwaj R et al. Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. PLoS Biol 2012; 10: e1001427.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Rajarajan P, Gil SE, Brennand KJ, Akbarian S . Spatial genome organization and cognition. Nat Rev Neurosci 2016; 17: 681–691.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Zweier M, Rauch A . The MEF2C-related and 5q14.3q15 microdeletion syndrome. Mol Syndromol 2012; 2: 164–170.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014; 506: 185–190.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013; 45: 1452–1458.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Malik AN, Vierbuchen T, Hemberg M, Rubin AA, Ling E, Couch CH et al. Genome-wide identification and characterization of functional neuronal activity-dependent enhancers. Nat Neurosci 2014; 17: 1330–1339.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Adachi M, Lin PY, Pranav H, Monteggia LM . Postnatal loss of Mef2c results in dissociation of effects on synapse number and learning and memory. Biol Psychiatry 2015; 80: 140–148.

    PubMed  PubMed Central  Google Scholar 

  67. Jakovcevski M, Ruan H, Shen EY, Dincer A, Javidfar B, Ma Q et al. Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory. J Neurosci 2015; 35: 5097–5108.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Jakovcevski M, Bharadwaj R, Straubhaar J, Gao G, Gavin DP, Jakovcevski I et al. Prefrontal cortical dysfunction after overexpression of histone deacetylase 1. Biol Psychiatry 2013; 74: 696–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Hering H, Sheng M . Dendritic spines: structure, dynamics and regulation. Nat Rev Neurosci 2001; 2: 880–888.

    CAS  PubMed  Google Scholar 

  70. Velázquez-Zamora DA, González-Ramírez MM, Beas-Zárate C, González-Burgos I . Egocentric working memory impairment and dendritic spine plastic changes in prefrontal neurons after NMDA receptor blockade in rats. Brain Res 2011; 1402: 101–108.

    PubMed  Google Scholar 

  71. Orner DA, Chen CC, Orner DE, Brumberg JC . Alterations of dendritic protrusions over the first postnatal year of a mouse: an analysis in layer VI of the barrel cortex. Brain Struct Funct 2014; 219: 1709–1720.

    PubMed  Google Scholar 

  72. Workman JL, Brummelte S, Galea LA . Postpartum corticosterone administration reduces dendritic complexity and increases the density of mushroom spines of hippocampal CA3 arbours in dams. J Neuroendocrinol 2013; 25: 119–130.

    CAS  PubMed  Google Scholar 

  73. Lyons GE, Micales BK, Schwarz J, Martin JF, Olson EN . Expression of mef2 genes in the mouse central nervous system suggests a role in neuronal maturation. TJ Neurosci 1995; 15: 5727–5738.

    CAS  Google Scholar 

  74. Lyons MR, Schwarz CM, West AE . Members of the myocyte enhancer factor 2 transcription factor family differentially regulate Bdnf transcription in response to neuronal depolarization. J Neurosci 2012; 32: 12780–12785.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Flavell SW, Kim TK, Gray JM, Harmin DA, Hemberg M, Hong EJ et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 2008; 60: 1022–1038.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Flavell SW, Cowan CW, Kim TK, Greer PL, Lin Y, Paradis S et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 2006; 311: 1008–1012.

    CAS  PubMed  Google Scholar 

  77. Akhtar MW, Kim MS, Adachi M, Morris MJ, Qi X, Richardson JA et al. in vivo analysis of MEF2 transcription factors in synapse regulation and neuronal survival. PLoS One 2012; 7: e34863.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Yamada T, Yang Y, Huang J, Coppola G, Geschwind DH, Bonni A . Sumoylated MEF2A coordinately eliminates orphan presynaptic sites and promotes maturation of presynaptic boutons. J Neurosci 2013; 33: 4726–4740.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Cole CJ, Mercaldo V, Restivo L, Yiu AP, Sekeres MJ, Han JH et al. MEF2 negatively regulates learning-induced structural plasticity and memory formation. Nat Neurosci 2012; 15: 1255–1264.

    CAS  PubMed  Google Scholar 

  80. Forrest MP, Hill MJ, Quantock AJ, Martin-Rendon E, Blake DJ . The emerging roles of TCF4 in disease and development. Trends Mol Med 2014; 20: 322–331.

    CAS  PubMed  Google Scholar 

  81. Rannals MD, Hamersky GR, Page SC, Campbell MN, Briley A, Gallo RA et al. Psychiatric risk gene transcription factor 4 regulates intrinsic excitability of prefrontal neurons via repression of SCN10a and KCNQ1. Neuron 2016; 90: 43–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Wei Q, Li M, Kang Z, Li L, Diao F, Zhang R et al. ZNF804A rs1344706 is associated with cortical thickness, surface area, and cortical volume of the unmedicated first episode schizophrenia and healthy controls. Am J Med Genet B Neuropsychiatr Genet 2015; 168B: 265–273.

    PubMed  Google Scholar 

  83. Hess JL, Quinn TP, Akbarian S, Glatt SJ . Bioinformatic analyses and conceptual synthesis of evidence linking ZNF804A to risk for schizophrenia and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2015; 168B: 14–35.

    PubMed  Google Scholar 

  84. McMeekin LJ, Lucas EK, Meador-Woodruff JH, McCullumsmith RE, Hendrickson RC, Gamble KL et al. Cortical PGC-1alpha-dependent transcripts are reduced in postmortem tissue from patients with schizophrenia. Schizophr Bull 2015; 42: 1009–1017.

    PubMed  PubMed Central  Google Scholar 

  85. Volk DW, Matsubara T, Li S, Sengupta EJ, Georgiev D, Minabe Y et al. Deficits in transcriptional regulators of cortical parvalbumin neurons in schizophrenia. Am J Psychiatry 2012; 169: 1082–1091.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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.

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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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