LncRNA RP5-998N21.4 promotes immune defense through upregulation of IFIT2 and IFIT3 in schizophrenia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA774735 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16576216_1.fastq.gz | Fastqsanger.gz | |||
| SRR16576216_2.fastq.gz | Fastqsanger.gz | |||
| SRR16576217_1.fastq.gz | Fastqsanger.gz | |||
| SRR16576217_2.fastq.gz | Fastqsanger.gz | |||
| SRR16576218_1.fastq.gz | Fastqsanger.gz |
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Project description:We recently identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA) RP5-998N21.4 by transcriptomic analysis of monozygotic twins discordant for schizophrenia. Importantly, we found that genes coexpressed with RP5-998N21.4 were enriched in immune defense-related biological processes in twin subjects and in RP5-998N21.4-overexpressing (OE) SK-N-SH cell lines. We then identified two genes encoding interferon-induced protein with tetratricopeptide repeat (IFIT) 2 and 3, which play an important role in immune defense, as potential targets of RP5-998N21.4 by integrative analysis of RP5-998N21.4OE-induced differentially expressed genes (DEGs) in SK-N-SH cells and RP5-998N21.4-coexpressed schizophrenia-associated DEGs from twin subjects. We further demonstrated that RP5-998N21.4 positively regulates the transcription of IFIT2 and IFIT3 by binding to their promoter regions and affecting their histone modifications. In addition, as a general nuclear coactivator, RMB14 (encoding RNA binding motif protein 14) was identified to facilitate the regulatory role of RP5-998N21.4 in IFIT2 and IFIT3 transcription.
2021-10-28 | GSE186598 | GEO
Project description:Schizophrenia is a complex polygenic disease that is affected by genetic, developmental, and environmental factors. Accumulating evidence indicates that environmental factors such as maternal infection and excessive prenatal neuroinflammation may contribute to the onset of schizophrenia by affecting epigenetic modification. We recently identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA) RP5-998N21.4 by transcriptomic analysis of monozygotic twins discordant for schizophrenia. Importantly, we found that genes coexpressed with RP5-998N21.4 were enriched in immune defense-related biological processes in twin subjects and in RP5-998N21.4-overexpressing (OE) SK-N-SH cell lines. We then identified two genes encoding an interferon-induced protein with tetratricopeptide repeat (IFIT) 2 and 3, which play an important role in immune defense, as potential targets of RP5-998N21.4 by integrative analysis of RP5-998N21.4OE-induced differentially expressed genes (DEGs) in SK-N-SH cells and RP5-998N21.4-coexpressed schizophrenia-associated DEGs from twin subjects. We further demonstrated that RP5-998N21.4 positively regulates the transcription of IFIT2 and IFIT3 by binding to their promoter regions and affecting their histone modifications. In addition, as a general nuclear coactivator, RMB14 (encoding RNA binding motif protein 14) was identified to facilitate the regulatory role of RP5-998N21.4 in IFIT2 and IFIT3 transcription. Finally, we observed that RP5-998N21.4OE can enhance IFIT2- and IFIT3-mediated immune defense responses through activation of signal transducer and activator of transcription 1 (STAT1) signaling pathway in U251 astrocytoma cells under treatment with the viral mimetic polyinosinic: polycytidylic acid (poly I:C). Taken together, our findings suggest that lncRNA RP5-998N21.4 is a critical regulator of immune defense, providing etiological and therapeutic implications for schizophrenia.
| S-EPMC8888552 | biostudies-literature
Project description:Interferon-induced protein with tetratricopeptide repeat 2 (IFIT2) is known for its antiviral activity and has recently been implicated in the defense against Mycobacterium tuberculosis (M. tb). This study employed global transcriptomics to investigate the downstream effects of IFIT2 induction in THP-1 macrophages infected with R179 M. tb, aiming to elucidate its role and downstream contributing factors that aid it in intracellular M. tb killing. Using a vector-based overexpression approach, IFIT2 expression was induced in THP-1 cells infected with R179 M. tb, followed by RNA extraction 12 hours postinfection and AmpliSeq-based targeted transcriptome sequencing. Bioinformatics analysis identified 282 differentially expressed genes (DEGs), of which 189 were upregulated and 90 were downregulated (FDR <0.05). Filtering for highly significant DEGs (|log2(fold change) | > 1.5) yielded 70 genes, predominantly upregulated, with functional enrichment in pathways such as defense response to viruses and cytokine-mediated signaling. Signaling pathway impact analysis highlighted pathway activation and inhibition of the tuberculosis (TB) pathway. RT-qPCR validation confirmed the upregulation of selected DEGs (ISG15, CMPK2, RSAD2, IFI44L, IFI44), corroborating the AmpliSeq data. This study provides comprehensive insights into the transcriptomic profile induced by IFIT2 in TB, revealing critical downstream contributors and pathways that underpin IFIT2’s ability to combat M. tb infection.
2025-05-14 | GSE297207 | GEO
Project description:IFit2 is highly induced in response to type I and type II interferons, dsRNA, LPS, viral and bacterial infections and it is als found in several chronic diseases.A possible role for the protein in cell proliferation, virion assembly/transport and microtubule dynamices was described. This study focus on IFIT2 proinflammatory cytokine response which might be involved in the development of septic shock. In the IFIT2 knockout mice gene expression levels before and after OVA challenge were analysed. Total RNA obtained from 3-4 male mutant mice (challenged/un-challenged) was compared to 4 wild type controls (challenged/unchallenged).
2014-05-02 | E-GEOD-39953 | biostudies-arrayexpress
Project description:IFit2 is highly induced in response to type I and type II interferons, dsRNA, LPS, viral and bacterial infections and it is als found in several chronic diseases.A possible role for the protein in cell proliferation, virion assembly/transport and microtubule dynamices was described. This study focus on IFIT2 proinflammatory cytokine response which might be involved in the development of septic shock. In the IFIT2 knockout mice gene expression levels before and after OVA challenge were analysed.
2014-05-02 | GSE39953 | GEO
Project description:This study examined the miRNA expression level in exosomal derived from the plasma of first episode schizophrenia (FOS) patients and Healthy controls (HC), and explored the the potential of exosomes as biomarkers for schizophrenia. This study examined the lncRNA expression level in exosomal derived from the plasma of first episode schizophrenia (FOS) patients and Healthy controls (HC), and explored the the potential of exosomes as biomarkers for schizophrenia. This study examined the mRNA expression level in exosomal derived from the plasma of first episode schizophrenia (FOS) patients and Healthy controls (HC), and explored the the potential of exosomes as biomarkers for schizophrenia.
2023-08-30 | GSE228881 | GEO
Project description:Cells infected by influenza virus mount a large-scale antiviral response and most cells ultimately initiate cell-death pathways in an attempt to suppress viral replication. We performed a CRISPR/Cas9-knockout selection designed to identify host factors required for replication following viral entry. We identified a large class of presumptive antiviral factors that unexpectedly act as important pro-viral enhancers during influenza virus infection. One of these, IFIT2, is an interferon-stimulated gene with well-established antiviral activity but limited mechanistic understanding. As opposed to suppressing infection, we show here that IFIT2 is instead repurposed by influenza virus to promote viral gene expression. CLIP‐seq demonstrated that IFIT2 binds directly to viral and cellular mRNAs in AU‐rich regions, with bound cellular transcripts enriched in interferon‐stimulated mRNAs. Polysome and ribosome profiling revealed that IFIT2 prevents ribosome pausing on bound mRNAs. Together, the data link IFIT2 binding to enhanced translational efficiency for viral and cellular mRNAs and ultimately viral replication. Our findings establish a model for the normal function of IFIT2 as a protein that increases translation of cellular mRNAs to support antiviral responses and explain how influenza virus uses this same activity to redirect a classically antiviral protein into a pro-viral effector.
2022-02-03 | GSE196010 | GEO
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.
2022-06-24 | GSE206720 | GEO
Project description:Recognition of non-self nucleic acids, including cytoplasmic dsDNA, dsRNA, or mRNAs lacking proper 5' cap structures, is critical for the induction of innate immunity against viruses. Here, we demonstrate that short 5’ untranslated regions (UTRs), a characteristic of many viral mRNAs, can also serve as molecular pattern for innate immune recognition via the interferon-induced proteins, IFIT2 and IFIT3. The IFIT2-IFIT3 heterodimer, formed through an intricate domain swap structure, mediates viral mRNA 5' end recognition, translation inhibition, and ultimately antiviral activity. Critically, 5' UTR lengths <50 nucleotides are necessary and sufficient to sensitize an mRNA to translation inhibition by the IFIT2-IFIT3 complex. Thus, diverse viruses whose mRNAs contain short 5’ UTRs, such as vesicular stomatitis virus and parainfluenza virus 3, are sensitive to IFIT2-IFIT3-mediated antiviral activity. Our work reveals a new size-restricted pattern of nucleic acid innate immune recognition for the selective repression of viral replication.
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