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

Biological Psychiatry
Jacob J MichaelsonAndrew A Pieper

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 lev...Continue Reading

Citations

Dec 5, 2018·BMC Molecular Biology·Leiah M Luoma, Fred B Berry
Sep 5, 2019·Frontiers in Cellular Neuroscience·Lauren Rylaarsdam, Alicia Guemez-Gamboa
Feb 23, 2019·Cold Spring Harbor Symposia on Quantitative Biology·Andrew A Pieper, Steven L McKnight
Sep 22, 2018·Neuropharmacology·Meghan O BlayaW Dalton Dietrich
May 27, 2021·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Claudia PisanuAlessio Squassina
May 16, 2018·Psychiatry Research·Leiah M LuomaScot E Purdon

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