Identification of the BRD1 interaction network and its impact on mental disorder risk
Transcription factors and miRNAs regulate gene expression on pre- and post-transcriptional levels, respectively. They are known to have large interaction networks and play important roles in e.g. cell differentiation and tissue development. This study explores the chromatin co-modifier, BRD1.
About the study
The bromodomain containing 1 (BRD1) gene has been implicated with transcriptional regulation, brain development, and susceptibility to schizophrenia and bipolar disorder. On a molecular level, the BRD1 protein functions as a chromatin co-modifier e.i. interacting in complexes with both proteins and DNA. In this study, we generated stable human cell lines expressing epitope tagged BRD1-S and BRD1-L and used these as discovery systems for identifying proteome-wide and genome-wide BRD1 interactions. We then integrated our functional molecular data with human genomic and transcriptomic data using available GWAS, exome-sequencing datasets as well as spatiotemporal transcriptomic datasets from the human brain.
We identified several novel protein interactions of BRD1, including isoform-specific interactions as well as proteins previously implicated with mental disorders. For example, we found that the BRD1-S isoform interacts with the histone methyltransferase, SUV420H1. This is a particularly interesting discovery, since exome sequencing in a family study of autism previously identified de novo mutations in the SUV420H1 gene.
We also performed chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) of BRD1-S and BRD1-L. We found that BRD1-S and BRD1-L primarily binds near transcription start sites of genes. In this study, 1540 and 823 genes were, respectively, identified to have BRD1-S and BRD1-L interaction with their promoter regions. We further showed that there is a correlation between BRD1-S and BRD1-L binding and the regulation in gene expression of these genes. By integrating our results with large transcriptomic data sets from human brain, we show that the identified BRD1 interactions are also likely to take place in the human brain. Furthermore, we integrated our interaction data with large datasets from genome-wide association studies, and show that the BRD1 interaction network (comprising protein and genomic interactions) is enriched for schizophrenia risk.
Collectively, the results presented in this paper suggest that BRD1 acts as a regulatory hub of large a schizophrenia risk network, which plays a role in many brain regions throughout life. Interestingly, our results suggest that BRD1-S is interacting more with schizophrenia risk genes compared to the BRD1-L isoform. However, we found an increased enrichment of schizophrenia risk genes when we combined the two interaction networks suggesting that both isoforms play a role in regulating schizophrenia risk genes. Furthermore, we provided evidence indicating that BRD1 play a role in regulating the expression of schizophrenia genes in human brain at mid-fetal stages and during childhood.
The article “Identification of the BRD1 interaction network and its impact on mental disorder risk” was published in Genome Med. 2016 May 3;8(1):53.
Facts about the study
- Proteome and genome-wide interaction networks were identified for two BRD1 isoforms; BRD1-S and BRD1-L.
- The BRD1 protein-protein network comprise proteins implicated with mental disorders e.g. SUV420H1
- The BRD1-S and BRD1-L bind near transcription start sites of 1540 and 823 genes, respectively.
- The BRD1 interaction network is enriched for schizophrenia risk genes
- BRD1 may play a role in regulating the expression of schizophrenia risk genes at midt fetal stages and during childhood
Further information
Tue Fryland, Postdoc, Department of Biomedicine, Aarhus University
E-mail: tue@biomed.au.dk