Journal article
Neuronal PAS Domain Proteins 1 and 3 Are Master Regulators of Neuropsychiatric Risk Genes
Biological psychiatry (1969), Vol.82(3), pp.213-223
08/01/2017
DOI: 10.1016/j.biopsych.2017.03.021
PMCID: PMC6901278
PMID: 28499489
Abstract
NPAS3 has been established as a robust genetic risk factor in major mental illness. In mice, loss of neuronal PAS domain protein 3 (NPAS3) impairs postnatal hippocampal neurogenesis, while loss of the related protein NPAS1 promotes it. These and other findings suggest a critical role for NPAS proteins in neuropsychiatric functioning, prompting interest in the molecular pathways under their control.
We used RNA sequencing coupled with chromatin immunoprecipitation sequencing to identify genes directly regulated by NPAS1 and NPAS3 in the hippocampus of wild-type, Npas1
, and Npas3
mice. Computational integration with human genetic and expression data revealed the disease relevance of NPAS-regulated genes and pathways. Specific findings were confirmed at the protein level by Western blot.
This is the first in vivo, transcriptome-scale investigation of genes regulated by NPAS1 and NPAS3. These transcription factors control an ensemble of genes that are themselves also major regulators of neuropsychiatric function. Specifically, Fmr1 (fragile X syndrome) and Ube3a (Angelman syndrome) are transcriptionally regulated by NPAS3, as is the neurogenesis regulator Notch. Dysregulation of these pathways was confirmed at the protein level. Furthermore, NPAS1/3 targets show increased human genetic burden for schizophrenia and intellectual disability.
Together, these data provide a clear, unbiased view of the full spectrum of genes regulated by NPAS1 and NPAS3 and show that these transcription factors are master regulators of neuropsychiatric function. These findings expose the molecular pathophysiology of NPAS1/3 mutations and provide a striking example of the shared, combinatorial nature of molecular pathways that underlie diagnostically distinct neuropsychiatric conditions.
Details
- Title: Subtitle
- Neuronal PAS Domain Proteins 1 and 3 Are Master Regulators of Neuropsychiatric Risk Genes
- Creators
- Jacob J Michaelson - Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Biomedical Engineering, University of Iowa College of Engineering, University of Iowa, Iowa City, Iowa; Department of Communication Sciences and Disorders, University of Iowa College of Liberal Arts and Sciences, University of Iowa, Iowa City, Iowa; Iowa Institute of Human Genetics, University of Iowa, Iowa City, Iowa; Genetics Cluster Initiative, University of Iowa, Iowa City, Iowa; The DeLTA Center, University of Iowa, Iowa City, Iowa; University of Iowa Informatics Initiative, University of Iowa, Iowa City, Iowa. Electronic address: Jacob-Michaelson@uiowa.eduMin-Kyoo Shin - Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IowaJin-Young Koh - Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IowaLeo Brueggeman - Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IowaAngela Zhang - Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IowaAaron Katzman - Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IowaLatisha McDaniel - Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IowaMimi Fang - Department of Biochemistry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IowaMiles Pufall - Department of Biochemistry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IowaAndrew A Pieper - Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Neurology, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa; Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Veterans Affairs, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa; Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa; Weill Cornell Autism Research Program, Weill Cornell Medicine, Cornell University, New York, New York
- Resource Type
- Journal article
- Publication Details
- Biological psychiatry (1969), Vol.82(3), pp.213-223
- Publisher
- United States
- DOI
- 10.1016/j.biopsych.2017.03.021
- PMID
- 28499489
- PMCID
- PMC6901278
- ISSN
- 0006-3223
- eISSN
- 1873-2402
- Grant note
- T32 GM007337 / NIGMS NIH HHS R01 MH105527 / NIMH NIH HHS
- Language
- English
- Date published
- 08/01/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Iowa Neuroscience Institute; Radiation Oncology; Biochemistry and Molecular Biology; Otolaryngology
- Record Identifier
- 9984024418602771
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