The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in schizophrenia
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ABSTRACT:
PROVIDER: PRJNA851810 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19786410_1.fastq.gz | Fastqsanger.gz | |||
| SRR19786410_2.fastq.gz | Fastqsanger.gz | |||
| SRR19786412_1.fastq.gz | Fastqsanger.gz | |||
| SRR19786412_2.fastq.gz | Fastqsanger.gz | |||
| SRR19786413_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:Genome-wide screening for DNA copy-number variations (CNVs) was conducted for ten pairs, a total of 20 cases, of affected siblings using oligonucleotide array-based CGH. We found negative symptoms were significantly more severe (p < 0.05) in the subgroup that harboring more genetic imbalance (n ≧ 13, n = number of CNV-disrupted genes) as compared with the subgroup with fewer CNVs (n ≦ 6), indicating the degree of genetic imbalance may influence the severity of schizophrenia negative symptoms. Four central nervous system (CNS) related genes including CCAAT/enhancer binding protein, delta (CEBPD, 8q11.21), retinoid X receptor, alpha (RXRA, 9q34.2), LIM homeobox protein 5 (LHX5, 12q24.13) and serine/threonine kinase 11 (STK11, 19p13.3) are recurrently (incidence ≧16.7%) disrupted by CNVs. Two genes, PVR (poliovirus receptor) and BU678720, are concordant deleted in one and two, respectively, pairs of co-affected siblings. However, we did not find significant association of this BU678720 and schizophrenia in a large case-control sample. We conclude that the high genetic loading of CNVs may as the underlying cause of schizophrenia negative symptoms, and the CNS-related genes revealed by this study warrants further investigation.
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