1. Genome-Scale Transcriptional Regulatory Network Models of Psychiatric and Neurodegenerative Disorders
- Author
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Paul Shannon, Leroy Hood, Carlo Colantuoni, Bijoya Basu, Cory C. Funk, Alex M. Casella, Nathan D. Price, Jocelynn R. Pearl, Seth A. Ament, Dani E Bergey, and Rediet Oshone
- Subjects
Male ,medicine.medical_specialty ,Histology ,Regulator ,DNA footprinting ,Single-nucleotide polymorphism ,Biology ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Gene Regulatory Networks ,Prefrontal cortex ,Psychiatry ,Gene ,Transcription factor ,030304 developmental biology ,0303 health sciences ,Neurodegenerative Diseases ,Cell Biology ,Human brain ,Genomics ,Neural stem cell ,medicine.anatomical_structure ,Female ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Summary 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.
- Published
- 2018