Identification of the BRD1 interaction network and its impact on mental disorder risk.
Identification of the BRD1 interaction network and its impact on mental disorder risk.
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DOI：
10.1186/s13073-016-0308-x
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发表时间：
2016-05-03
期刊：
影响因子：
12.3
通讯作者：
Børglum AD
中科院分区：
文献类型：
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作者：
Fryland T;Christensen JH;Pallesen J;Mattheisen M;Palmfeldt J;Bak M;Grove J;Demontis D;Blechingberg J;Ooi HS;Nyegaard M;Hauberg ME;Tommerup N;Gregersen N;Mors O;Corydon TJ;Nielsen AL;Børglum AD
含溴结构域1（BRD 1）基因与转录调控、大脑发育以及精神分裂症和双相情感障碍的易感性有关。为了进一步了解BRD 1及其在精神障碍中的作用，我们表征了BRD 1亚型BRD 1-S和BRD 1-L的蛋白质和染色质相互作用。产生表达表位标记的BRD 1-S和BRD 1-L的稳定的人细胞系，并用作鉴定蛋白质和染色质相互作用的发现系统。蛋白质-蛋白质相互作用使用免疫共沉淀法随后质谱法鉴定，染色质相互作用使用染色质免疫沉淀法随后下一代测序鉴定。基因表达谱和差异表达的基因进行了鉴定后，上调和下调BRD 1表达，使用微阵列。使用可用的GWAS、外显子组测序数据集以及来自人脑的时空转录组数据集，将所呈现的功能分子数据与人类基因组和转录组数据整合。我们提出了几种新的蛋白质相互作用的BRD 1，包括异构体特异性的相互作用，以及蛋白质先前牵连的精神障碍。通过BRD 1-S和BRD 1-L染色质免疫沉淀，然后进行下一代测序，我们分别鉴定了与1540和823个基因的启动子区域的结合，并显示了BRD 1-S和BRD 1-L结合与基因表达调控之间的相关性。发现所鉴定的BRD 1相互作用网络主要与人脑中的BRD 1 mRNA共表达，并且富集了涉及基因表达和脑功能的途径。通过询问来自全基因组关联研究的大数据集，我们进一步证明了BRD 1相互作用网络对于精神分裂症风险是丰富的。我们的研究结果表明，BRD 1与染色质重塑蛋白（如PBRM 1）以及组蛋白修饰剂（如MYST 2和SUV 420 H1）相互作用。我们发现BRD 1主要与转录起始位点紧密结合，并调节许多基因的表达，其中许多基因与大脑发育和精神障碍的易感性有关。我们的研究结果表明，BRD 1作为一个全面的精神分裂症风险网络中的调节中心，在整个生命过程中在许多大脑区域发挥作用，涉及例如纹状体，海马和杏仁核在中期胎儿阶段。本文的在线版本（doi：10.1186/s13073-016-0308-x）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s13073-016-0308-x) contains supplementary material, which is available to authorized users.