Abstract
BackgroundThe 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.MethodsStable 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.ResultsWe 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0308-x) contains supplementary material, which is available to authorized users.
Highlights
The bromodomain containing 1 (BRD1) gene has been implicated with transcriptional regulation, brain development, and susceptibility to schizophrenia and bipolar disorder
By co-immunoprecipitations, followed by identification of associated proteins using nanoLC coupled to a LTQ Orbitrap mass spectrometry (MS)/MS system (Fig. 1a–c), we identified 24 and 16 Protein-protein interaction (PPI) for BRD1-S and BRD1-L, respectively (Table 1)
Our finding that histone H3 interacts with BRD1-L (Table 1) is in line with a previous study that identified the unmodified N-tail of histone H3 to interact with the PHD1 domain of BRD1 [50]
Summary
The bromodomain containing 1 (BRD1) gene has been implicated with transcriptional regulation, brain development, and susceptibility to schizophrenia and bipolar disorder. A focused promoter ChIP-on-chip (chromatin immunoprecipitation combined with microarray analysis) of co-expressed epitope tagged BRD1 and MYST2 in human K562 cells identified a large overlap in target genes between the two proteins suggesting a pivotal role of the BRD1/MYST2 complex in transcriptional regulation [7]. To gain more knowledge about the biological functions of BRD1 and how these might be involved in the pathogenesis of schizophrenia and related mental disorders, we sought in the present study to identify and analyze the BRD1 interaction network, encompassing BRD1-S and BRD1-L protein-protein interactions (PPIs) and chromatin interactions as well as genes being regulated upon up- or downregulation of BRD1. We interrogated large GWAS datasets and found that the BRD1 interaction network is enriched for schizophrenia risk
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