A protein interaction network of mental disorder factors in neural stem cells

Mental disorders (MDs) such as intellectual disability (ID), autism spectrum disabilities (ASD) and schizophrenia have a strong genetic component. Recently, many gene mutations associated with these MDs have been identified by high-throughput sequencing technology. A substantial fraction of these mutations is in genes encoding proteins involved in transcriptional regulation. It is unclear whether different MD-associated transcriptional regulators act in the same gene regulatory network. Such information is important to appreciate the underlying etiology of an MD and the molecular relatedness of different MDs. Physical interaction between transcriptional regulators is a strong predictor for their cooperation in gene regulation. Here, we purified several MD-associated transcriptional regulators from neural stem cells, identified their interaction partners by mass spectrometry and assembled a protein interaction network containing over 200 proteins. The interaction network is enriched for protein factors associated with ID, ASD or schizophrenia and enriched for protein factors encoded by evolutionary constrained genes. Our network thereby provides molecular connections between established MD factors and a discovery tool for novel MD genes. We identified interactions between many transcriptional regulators with a different MD association. We show that network factors preferentially co-localize on the genome and cooperate in the regulation of disease-relevant genes to explain overlapping phenotypes in different syndromes. Our results suggest that the observed transcriptional regulators associated with ID, schizophrenia or ASD are part of the same transcriptional network. We find that the severity of mutations in network factors increased with the severity of the associated MD, suggesting that the level of disruption of a common transcriptional network affects mental disorder outcome.