title: The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice.
abstract: The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative.
  
  
  
  This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1+/-mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters.
  
  
  
  Brd1+/-mice displayed cerebral histone H3K14 hypoacetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNA-sequencing analyses of cortical and striatal micropunches from Brd1+/-and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [Cacna1c and Cacnb2], cholinergic muscarinic receptor 4 [Chrm4)], dopamine receptor D2[Drd2], and transcription factor 4 [Tcf4]). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g., glutamatergic, monoaminergic, calcium, cyclic adenosine monophosphate [cAMP], dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa [DARPP-32], and cAMP responsive element binding protein signaling [CREB]).
  
  
  
  Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic, chromatin interactomic, and brain transcriptomic.
authors.affiliation: Departments of Biomedicine, Aarhus; iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus; H. Lundbeck A/S, Synaptic Transmission, Valby, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Qvist
authors.affiliation: Departments of Biomedicine, Aarhus; iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus.
authors.forename: Jane Hvarregaard
authors.initials: JH
authors.lastname: Christensen
authors.affiliation: Departments of Biomedicine, Aarhus.
authors.forename: Irina
authors.initials: I
authors.lastname: Vardya
authors.affiliation: Departments of Biomedicine, Aarhus; iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus.
authors.forename: Anto Praveen
authors.initials: AP
authors.lastname: Rajkumar
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Valby, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.affiliation: Departments of Biomedicine, Aarhus; iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus.
authors.forename: Veerle
authors.initials: V
authors.lastname: Paternoster
authors.affiliation: Molecular Biology and Genetics, Aarhus.
authors.forename: Ernst-Martin
authors.initials: EM
authors.lastname: Füchtbauer
authors.affiliation: Departments of Biomedicine, Aarhus; iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Pallesen
authors.affiliation: Departments of Biomedicine, Aarhus; iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus.
authors.forename: Tue
authors.initials: T
authors.lastname: Fryland
authors.affiliation: Departments of Biomedicine, Aarhus; Department of Health Science and Technology, Aalborg University, Aalborg.
authors.forename: Mads
authors.initials: M
authors.lastname: Dyrvig
authors.affiliation: Departments of Biomedicine, Aarhus; iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus.
authors.forename: Mads Engel
authors.initials: ME
authors.lastname: Hauberg
authors.affiliation: Departments of Biomedicine, Aarhus.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Lundsberg
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Valby, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Fejgin
authors.affiliation: Departments of Biomedicine, Aarhus; iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus.
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.affiliation: Departments of Biomedicine, Aarhus.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Stereology and EM Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University, Aarhus.
authors.forename: Jens Randel
authors.initials: JR
authors.lastname: Nyengaard
authors.affiliation: iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus; Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Valby, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Didriksen
authors.affiliation: Departments of Biomedicine, Aarhus; iSEQ, Centre for Integrative Sequencing, Aarhus; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus. Electronic address: anders@biomed.au.dk.
authors.forename: Anders Dupont
authors.initials: AD
authors.lastname: Børglum
mesh_terms: D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D001522:Behavior, Animal / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D007395:Interneurons / Q000502:physiology; D051379:Mice; D012559:Schizophrenia / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*; D000092468:Bromodomain Containing Proteins
chemical_list: D004298:Dopamine; D051548:Histone Acetyltransferases; D006657:Histones; D012701:Serotonin; C562256:BRD1 protein, mouse; D000092468:Bromodomain Containing Proteins
keywords: BRD1; Behavior; Cyclic AMP response element-binding protein (CREB); DARPP-32 signaling; Electrophysiology; Knockout mouse; Monoaminergic neurotransmission; RNAseq; Schizophrenia