Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia.
Abolfazl Doostparast Torshizi, Chris Armoskus, Hanwen Zhang, Marc P Forrest, Siwei Zhang, Tade Souaiaia, Oleg V Evgrafov, James A Knowles, Jubao Duan, Kai Wang
Author Information
Abolfazl Doostparast Torshizi: Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. ORCID
Chris Armoskus: College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA. ORCID
Hanwen Zhang: Center for Psychiatric Genetics, North Shore University Health System, Evanston, IL 60201, USA.
Marc P Forrest: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. ORCID
Siwei Zhang: Center for Psychiatric Genetics, North Shore University Health System, Evanston, IL 60201, USA. ORCID
Tade Souaiaia: College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
Oleg V Evgrafov: College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
James A Knowles: College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA. ORCID
Jubao Duan: Center for Psychiatric Genetics, North Shore University Health System, Evanston, IL 60201, USA. ORCID
Kai Wang: Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. ORCID
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 as a top candidate MR that may be dysregulated in SCZ. We validated as a MR through enrichment analysis of -binding sites in induced pluripotent stem cell (hiPSC)-derived neurons and in neuroblastoma cells. We further validated the predicted targets by knocking down in hiPSC-derived neural progenitor cells (NPCs) and glutamatergic neurons (Glut_Ns). The perturbed 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 may serve as a MR of a gene network dysregulated in SCZ at early stages of neurodevelopment.
