Abstract
Tissue-specific reverse engineering of transcriptional networks has uncovered master regulators (MRs) of cellular networks in various cancers, yet the application of this method to neuropsychiatric disorders is largely unexplored. Here, using RNA-Seq data on postmortem dorsolateral prefrontal cortex (DLPFC) from schizophrenia (SCZ) patients and control subjects, we deconvoluted the transcriptional network to identify transcriptional MRs that mediate expression of a large body of target genes. Together with an independent RNA-Seq data on cultured primary neuronal cells derived from olfactory neuroepithelium, we identified TCF4, a leading SCZ risk locus implicated by genome-wide association studies, as a candidate MR dysregulated in SCZ. We validated the dysregulated TCF4-related transcriptional network through examining the transcription factor binding footprints inferred from human induced pluripotent stem cell (hiPSC)-derived neuronal ATAC-Seq data and direct binding sites obtained from ChIP-seq data in SH-SY5Y cells. The predicted TCF4 regulons were enriched for genes showing transcriptomic changes upon knockdown of TCF4 in hiPSC-derived neural progenitor cells (NPC) and glutamatergic neurons (Glut_N), in which the hiPSC cell line was sampled from a SCZ patient. The altered TCF4 gene network perturbations in NPC, as compared to that in Glut_N, was more similar to the expression differences in the TCF4 gene network observed in the DLPFC of individuals with SCZ. Moreover, TCF4-associated gene expression changes in NPC were more enriched for pathways involved in neuronal activity, genome-wide significant SCZ risk genes, and SCZ-associated de novo mutations. Our results suggest that TCF4 serves as a MR of a gene network that confers susceptibility to SCZ at early stage of neurodevelopment, highlighting the importance of network dysregulation involving hundreds of genes in conferring susceptibility to neuropsychiatric diseases.
