The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in schizophrenia

ABSTRACT: Long noncoding RNAs (lncRNAs) play multifaceted roles in regulating molecular networks that underlie normal brain function and the complex etiology of neuropsychiatric disorders. One example is the human neuronal lncRNA GOMAFU, which was reported to display abnormal expression in schizophrenia (SCZ) postmortem brains, regulate alternative splicing of SCZ risk gene transcripts, and harbor genetic variates contributing to the risk of SCZ. However, functional targets and molecular networks regulated by GOMAFU have not been determined. How GOMAFU dysregulation contributes to SCZ pathogenesis remains elusive. Here we report that GOMAFU is a novel modulator of neuronal interferon (IFN) response pathways. We found ectopic changes of GOMAFU in a brain region-specific manner from transcriptomic profiling datasets derived from multiple SCZ cohorts. Using CRISPR-Cas9 to delete the GOMAFU promoter, we identified hundreds of human neuronal GOMAFU targets in various SCZ-affected molecular pathways, with the most striking effects on upregulation of numerous genes enriched in IFN signaling pathways. In addition, GOMAFU targets in the IFN pathways are differentially affected in SCZ postmortem brain regions and negatively associated with GOMAFU abundance. Furthermore, acute exposure to IFN- caused a marked decline of GOMAFU, leading to selective upregulation of a subclass of GOMAFU targets in stress and immune response pathways, which are also affected in SCZ brains and form a highly interactive molecular network. Together, our studies revealed novel roles of GOMAFU in governing the neuronal IFN pathways and suggest that GOMAFU dysregulation may contribute to the etiological neuroinflammatory responses in SCZ brain neurons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206720 | GEO | 2022/06/24

REPOSITORIES: GEO