Moen M J, Adams H H H, Brandsma J H, Dekkers D H W, Akinci U, Karkampouna S, Quevedo M, Kockx C E M, Ozgür Z, van IJcken W F J, Demmers J, Poot R A
Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
Center for Proteomics, Erasmus MC, Rotterdam, The Netherlands.
Transl Psychiatry. 2017 Apr 4;7(4):e1082. doi: 10.1038/tp.2017.52.
Mental disorders (MDs) such as intellectual disability (ID), autism spectrum disorders (ASD) and schizophrenia have a strong genetic component. Recently, many gene mutations associated with ID, ASD or schizophrenia have been identified by high-throughput sequencing. A substantial fraction of these mutations are in genes encoding transcriptional regulators. Transcriptional regulators associated with different MDs but acting in the same gene regulatory network provide information on the molecular relation between MDs. Physical interaction between transcriptional regulators is a strong predictor for their cooperation in gene regulation. Here, we biochemically purified transcriptional regulators from neural stem cells, identified their interaction partners by mass spectrometry and assembled a protein interaction network containing 206 proteins, including 68 proteins mutated in MD patients and 52 proteins significantly lacking coding variation in humans. Our network shows molecular connections between established MD proteins and provides a discovery tool for novel MD genes. Network proteins preferentially co-localize on the genome and cooperate in disease-relevant gene regulation. Our results suggest that the observed transcriptional regulators associated with ID, ASD or schizophrenia are part of a transcriptional network in neural stem cells. We find that more severe mutations in network proteins are associated with MDs that include lower intelligence quotient (IQ), suggesting that the level of disruption of a shared transcriptional network correlates with cognitive dysfunction.
智力残疾（ID）、自闭症谱系障碍（ASD）和精神分裂症等精神障碍具有很强的遗传成分。最近，通过高通量测序已鉴定出许多与ID、ASD或精神分裂症相关的基因突变。这些突变中有很大一部分存在于编码转录调节因子的基因中。与不同精神障碍相关但作用于同一基因调控网络的转录调节因子提供了关于精神障碍之间分子关系的信息。转录调节因子之间的物理相互作用是它们在基因调控中合作的有力预测指标。在此，我们从神经干细胞中生物化学纯化了转录调节因子，通过质谱鉴定了它们的相互作用伙伴，并构建了一个包含206种蛋白质的蛋白质相互作用网络，其中包括68种在精神障碍患者中发生突变的蛋白质和52种在人类中显著缺乏编码变异的蛋白质。我们的网络展示了已确定的精神障碍相关蛋白质之间的分子联系，并为新型精神障碍基因提供了一个发现工具。网络蛋白质优先在基因组上共定位，并在与疾病相关的基因调控中协同作用。我们的结果表明，观察到的与ID、ASD或精神分裂症相关的转录调节因子是神经干细胞中转录网络的一部分。我们发现网络蛋白质中更严重的突变与包括较低智商（IQ）在内的精神障碍相关，这表明共享转录网络的破坏程度与认知功能障碍相关。
