期刊
CELL SYSTEMS
卷 8, 期 2, 页码 122-+出版社
CELL PRESS
DOI: 10.1016/j.cels.2019.01.002
关键词
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资金
- National Science Foundation (United States)
- NARSAD Young Investigator Award from the Brain and Behavior Research Foundation
- NIGMS Center for Systems Biology at the Institute for Systems Biology [P50 GM076547]
- Big Data for Discovery Science Center of the NIH Big Data to Knowledge program [U54 EB020406]
- NIA (United States) [U01 AG046139]
- University of Maryland School of Medicine (United States)
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.
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