Genome-Scale Transcriptional Regulatory Network Models of Psychiatric and Neurodegenerative Disorders

Jocelynn R. Pearl, Carlo Colantuoni, Dani E. Bergey, Cory C. Funk, Paul Shannon, Bijoya Basu, Alex M. Casella, Rediet T. Oshone, Leroy Hood, Nathan D. Price, Seth A. Ament

Research output: Contribution to journalArticlepeer-review

Abstract

Transcriptional regulatory changes in the developing and adult brain are prominent features of brain diseases, but the involvement of specific transcription factors (TFs) remains poorly understood. We integrated brain-specific DNase footprinting and TF-gene co-expression to reconstruct a transcriptional regulatory network (TRN) model for the human brain. We identified key regulator TFs whose predicted target genes were enriched for differentially expressed genes in the prefrontal cortex of individuals with psychiatric and neurodegenerative diseases. Many of these TFs were further implicated in the same diseases through disruption of their binding sites by disease-associated SNPs and associations of TF loci with disease risk. Using primary human neural stem cells, we validated network predictions that link the TF POU3F2 to schizophrenia and bipolar disorder via both cis- and trans-acting mechanisms. Our models of brain-specific TF binding sites and target genes provide a resource for network analysis of brain diseases. Transcriptional regulatory changes in the developing and adult brain are prominent features of brain diseases, but roles for specific transcription factors (TFs) are poorly understood. We reconstructed a model for the binding sites and target genes of 741 TFs in the human brain and predicted key regulators of genetic and genomic changes in psychiatric and neurodegenerative disorders. In neural stem cells, the TF POU3F2 regulated hundreds of genes enriched for neocortical gene expression changes in schizophrenia and bipolar disorder.

Original languageEnglish (US)
Pages (from-to)122-135.e7
JournalCell Systems
Volume8
Issue number2
DOIs
StatePublished - Feb 27 2019

Keywords

  • POU3F2
  • neurodegenerative disease
  • psychiatric disease
  • transcription factor network
  • transcriptional regulatory network

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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