@article{9957590c8a9c4cb8a245f8795bcdebd3,
title = "Genome-Scale Transcriptional Regulatory Network Models of Psychiatric and Neurodegenerative Disorders",
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.",
keywords = "POU3F2, neurodegenerative disease, psychiatric disease, transcription factor network, transcriptional regulatory network",
author = "Pearl, {Jocelynn R.} and Carlo Colantuoni and Bergey, {Dani E.} and Funk, {Cory C.} and Paul Shannon and Bijoya Basu and Casella, {Alex M.} and Oshone, {Rediet T.} and Leroy Hood and Price, {Nathan D.} and Ament, {Seth A.}",
note = "Funding Information: The authors thank Patrick Paddison, Yu Ding, and Chad Toledo (Fred Hutchinson Cancer Research Center) for graciously providing human neural stem cells; Elizabeth Gray, Daniel Stetson, and Kathleen Pestal (University of Washington) for providing LentiCRISPR plasmids and protocols; John Kelsoe and Tatyana Shekhtman (University of California, San Diego) for providing genomic DNA for promoter cloning of VRK2; and Nathaniel Peters (W.M. Keck Microscopy Center, University of Washington) for providing immunofluorescence imaging and advice. The author also thank Victor Felix (who maintained resources available at amentlab.igs.umaryland.edu ) and Gene Robinson for helpful discussion and providing comments on an early version of this manuscript. This work was supported by a National Science Foundation (United States) Graduate Research Fellowship (J.R.P.), an NARSAD Young Investigator Award from the Brain and Behavior Research Foundation (S.A.A.), the NIGMS Center for Systems Biology at the Institute for Systems Biology ( P50 GM076547 ; L.H. and N.D.P.), the Big Data for Discovery Science Center of the NIH Big Data to Knowledge program (U54 EB020406; N.D.P. and L.H.), a contract from the NIA (United States; U01 AG046139 ; N.D.P.), and seed funding from the University of Maryland School of Medicine (United States; S.A.A.). Funding Information: The authors thank Patrick Paddison, Yu Ding, and Chad Toledo (Fred Hutchinson Cancer Research Center) for graciously providing human neural stem cells; Elizabeth Gray, Daniel Stetson, and Kathleen Pestal (University of Washington) for providing LentiCRISPR plasmids and protocols; John Kelsoe and Tatyana Shekhtman (University of California, San Diego) for providing genomic DNA for promoter cloning of VRK2; and Nathaniel Peters (W.M. Keck Microscopy Center, University of Washington) for providing immunofluorescence imaging and advice. The author also thank Victor Felix (who maintained resources available at amentlab.igs.umaryland.edu) and Gene Robinson for helpful discussion and providing comments on an early version of this manuscript. This work was supported by a National Science Foundation (United States) Graduate Research Fellowship (J.R.P.), an NARSAD Young Investigator Award from the Brain and Behavior Research Foundation (S.A.A.), the NIGMS Center for Systems Biology at the Institute for Systems Biology (P50 GM076547; L.H. and N.D.P.), the Big Data for Discovery Science Center of the NIH Big Data to Knowledge program (U54 EB020406; N.D.P. and L.H.), a contract from the NIA (United States; U01 AG046139; N.D.P.), and seed funding from the University of Maryland School of Medicine (United States; S.A.A.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = feb,
day = "27",
doi = "10.1016/j.cels.2019.01.002",
language = "English (US)",
volume = "8",
pages = "122--135.e7",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "2",
}