The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in neuropsychiatric diseases

• Type of Material: Article
• Authors: Peng Teng, Emory University; Yangping Li, Emory University; Li Ku, Emory University; Feng Wang, Emory University; David R. Goldsmith, Emory University; Zhexing Wen, Emory University; Bing Yao, Emory University; Yue Feng, Emory University
• Language: English
• Date: 2023-06-08
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Published by Elsevier Inc
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1016%2Fj.bbi.2023.06.009
• Title of Journal or Parent Work: Brain, Behavior, and Immunity
• Volume: 112
• Issue: August 2023
• Start Page: 175
• End Page: 187
• Grant/Funding Information: This work was supported by NIH grants R01NS110110, R01NS118819, and R01NS093016 to YF; R01AG062577, R01MH117122, and R01AG064786 to B.Y.; R01AG065611 and R21MH12711 to W.Z.
• Keywords: Neuropsychiatric Disorders; long non-coding RNA; GOMAFU; Neuroinflammation; Schizophrenia
• Research Categories: Psychology, Psychobiology; Biology, Genetics; Biology, Neuroscience

Abstract

Long noncoding RNAs (lncRNAs) play multifaceted roles in regulating brain gene networks. LncRNA abnormalities are thought to underlie the complex etiology of numerous neuropsychiatric disorders. One example is the human lncRNA gene GOMAFU, which is found dysregulated in schizophrenia (SCZ) postmortem brains and harbors genetic variants that contribute to the risk of SCZ. However, transcriptome-wide biological pathways regulated by GOMAFU have not been determined. How GOMAFU dysregulation contributes to SCZ pathogenesis remains elusive. Here we report that GOMAFU is a novel suppressor of human neuronal interferon (IFN) response pathways that are hyperactive in the postmortem SCZ brains. We analyzed recently released transcriptomic profiling datasets in clinically relevant brain areas derived from multiple SCZ cohorts and found brain region-specific dysregulation of GOMAFU. Using CRISPR-Cas9 to delete the GOMAFU promoter in a human neural progenitor cell model, we identified transcriptomic alterations caused by GOMAFU deficiency in pathways commonly affected in postmortem brains of SCZ and autism spectrum disorder (ASD), with the most striking effects on upregulation of numerous genes underlying IFN signaling. In addition, expression levels of GOMAFU target genes in the IFN pathway are differentially affected in SCZ brain regions and negatively associated with GOMAFU alterations. Furthermore, acute exposure to IFN-γ causes a rapid decline of GOMAFU and activation of a subclass of GOMAFU targets in stress and immune response pathways that are affected in SCZ brains, which form a highly interactive molecular network. Together, our studies unveiled the first evidence of lncRNA-governed neuronal response pathways to IFN challenge and suggest that GOMAFU dysregulation may mediate environmental risks and contribute to etiological neuroinflammatory responses by brain neurons of neuropsychiatric diseases.