title: Identification of the BRD1 interaction network and its impact on mental disorder risk.
abstract: The bromodomain containing 1 (BRD1) gene has been implicated with transcriptional regulation, brain development, and susceptibility to schizophrenia and bipolar disorder. To advance the understanding of BRD1 and its role in mental disorders, we characterized the protein and chromatin interactions of the BRD1 isoforms, BRD1-S and BRD1-L.
  
  
  
  Stable human cell lines expressing epitope tagged BRD1-S and BRD1-L were generated and used as discovery systems for identifying protein and chromatin interactions. Protein-protein interactions were identified using co-immunoprecipitation followed by mass spectrometry and chromatin interactions were identified using chromatin immunoprecipitation followed by next generation sequencing. Gene expression profiles and differentially expressed genes were identified after upregulating and downregulating BRD1 expression using microarrays. The presented functional molecular data were integrated with human genomic and transcriptomic data using available GWAS, exome-sequencing datasets as well as spatiotemporal transcriptomic datasets from the human brain.
  
  
  
  We present several novel protein interactions of BRD1, including isoform-specific interactions as well as proteins previously implicated with mental disorders. By BRD1-S and BRD1-L chromatin immunoprecipitation followed by next generation sequencing we identified binding to promoter regions of 1540 and 823 genes, respectively, and showed correlation between BRD1-S and BRD1-L binding and regulation of gene expression. The identified BRD1 interaction network was found to be predominantly co-expressed with BRD1 mRNA in the human brain and enriched for pathways involved in gene expression and brain function. By interrogation of large datasets from genome-wide association studies, we further demonstrate that the BRD1 interaction network is enriched for schizophrenia risk.
  
  
  
  Our results show that BRD1 interacts with chromatin remodeling proteins, e.g. PBRM1, as well as histone modifiers, e.g. MYST2 and SUV420H1. We find that BRD1 primarily binds in close proximity to transcription start sites and regulates expression of numerous genes, many of which are involved with brain development and susceptibility to mental disorders. Our findings indicate that BRD1 acts as a regulatory hub in a comprehensive schizophrenia risk network which plays a role in many brain regions throughout life, implicating e.g. striatum, hippocampus, and amygdala at mid-fetal stages.
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Tue
authors.initials: T
authors.lastname: Fryland
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Christensen
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Pallesen
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Research Unit for Molecular Medicine, Aarhus University Hospital, 8200, Skejby, Denmark.
authors.forename: Johan
authors.initials: J
authors.lastname: Palmfeldt
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen N, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Bak
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.|Bioinformatics Research Centre (BiRC, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Grove
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Ditte
authors.initials: D
authors.lastname: Demontis
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.
authors.forename: Jenny
authors.initials: J
authors.lastname: Blechingberg
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Hong Sain
authors.initials: HS
authors.lastname: Ooi
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Mads E
authors.initials: ME
authors.lastname: Hauberg
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen N, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: Research Unit for Molecular Medicine, Aarhus University Hospital, 8200, Skejby, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Gregersen
authors.affiliation: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.|Research Department P, Aarhus University Hospital, 8240, Risskov, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Corydon
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Anders L
authors.initials: AL
authors.lastname: Nielsen
authors.affiliation: Department of Biomedicine, Aarhus University, Building 1242, Bartholins Allé 6, 8000, Aarhus C, Denmark. anders@biomed.au.dk.|iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus C, Denmark. anders@biomed.au.dk.|iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000, Aarhus C, Denmark. anders@biomed.au.dk.|Research Department P, Aarhus University Hospital, 8240, Risskov, Denmark. anders@biomed.au.dk.
authors.forename: Anders D
authors.initials: AD
authors.lastname: Børglum
mesh_terms: D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006801:Humans; D013058:Mass Spectrometry; D001523:Mental Disorders / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping / Q000379:methods*; D020033:Protein Isoforms / Q000378:metabolism; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D009687:Nuclear Proteins; D020033:Protein Isoforms; D020543:Proteome; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins
keywords: Chip-seq; Functional genomics; Interactome; Mental disorders; Proteomics; Regulome; Schizophrenia