Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia

Sci Adv. 2019 Sep 11;5(9):eaau4139. doi: 10.1126/sciadv.aau4139. eCollection 2019 Sep.


Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia (SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and another on cultured olfactory neuroepithelium, we deconvolved the transcriptional networks and identified TCF4 as a top candidate MR that may be dysregulated in SCZ. We validated TCF4 as a MR through enrichment analysis of TCF4-binding sites in induced pluripotent stem cell (hiPSC)-derived neurons and in neuroblastoma cells. We further validated the predicted TCF4 targets by knocking down TCF4 in hiPSC-derived neural progenitor cells (NPCs) and glutamatergic neurons (Glut_Ns). The perturbed TCF4 gene network in NPCs was more enriched for pathways involved in neuronal activity and SCZ-associated risk genes, compared to Glut_Ns. Our results suggest that TCF4 may serve as a MR of a gene network dysregulated in SCZ at early stages of neurodevelopment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Cells, Cultured
  • Gene Regulatory Networks*
  • Genetic Predisposition to Disease
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Male
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Neuroepithelial Cells / metabolism*
  • Neuroepithelial Cells / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Olfactory Mucosa / metabolism*
  • Olfactory Mucosa / pathology
  • Prefrontal Cortex / metabolism*
  • Prefrontal Cortex / pathology
  • Schizophrenia / genetics*
  • Schizophrenia / pathology
  • Transcription Factor 4 / genetics
  • Transcription Factor 4 / metabolism*


  • TCF4 protein, human
  • Transcription Factor 4