Les protéines 1 et 3 du domaine PAS neuronal sont les régulateurs maîtres des gènes de risque neuropsychiatrique

Aperçu: G.M.

Ensemble, ces données fournissent une vision claire et impartiale de l'ensemble des gènes régulés par NPAS1 et NPAS3 et montrent que ces facteurs de transcription sont des régulateurs maîtres de la fonction neuropsychiatrique. Ces résultats exposent la pathophysiologie moléculaire des mutations NPAS1 / 3 et fournissent un exemple frappant de la nature combinatoire des voies moléculaires qui sous-tendent des états neuropsychiatriques diagnostiqués distinctement.

Biol Psychiatry. 2017 Apr 6. pii: S0006-3223(17)31460-9. doi: 10.1016/j.biopsych.2017.03.021.

Neuronal PAS Domain Proteins 1 and 3 Are Master Regulators of Neuropsychiatric Risk Genes

Michaelson JJ¹, Shin MK², Koh JY², Brueggeman L², Zhang A², Katzman A², McDaniel L², Fang M³, Pufall M³, Pieper AA⁴.

Author information

1

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.edu.

2

Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa.

3

Department of Biochemistry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa.

4

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.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PMID: 28499489

DOI: 10.1016/j.biopsych.2017.03.021