Emerging Role of Chimeric RNAs in Cell Plasticity and Adaptive Evolution of Cancer Cells

Frenkel‐Morgenstern

2022

Cells

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In cancers and other complex diseases, the fusion of two genes can lead to the production of chimeric RNAs, which are associated with disease development. Several recurrent chimeric RNAs are expressed in different cancers and are thus used for clinical cancer diagnosis. Rheumatoid arthritis (RA) is an immune-mediated joint disorder resulting in synovial inflammation and joint destruction. Despite advances in therapy, many patients do not respond to treatment and present persistent inflammation. Understanding the landscape of chimeric RNA expression in RA patients could provide a better insight into RA pathogenesis, which might provide better treatment strategies and tailored therapies. Accordingly, we analyzed the publicly available RNA-seq data of synovium tissue from 151 RA patients and 28 healthy controls and were able to identify 37 recurrent chimeric RNAs found to be expressed in at least 3 RA samples. Furthermore, the parental genes of these 37 recurrent chimeric RNAs were found to be differentially expressed and enriched in immune-related processes, such as adaptive immune response and the positive regulation of B-cell activation. Interestingly, the appearance of 5 coding and 23 non-coding chimeric RNAs might be associated with regulating their parental gene expression, leading to the generation of dysfunctional immune responses, such as inflammation and bone destruction. Therefore, in this paper, we present the first study to demonstrate the novel chimeric RNAs that are highly expressed and functional in RA.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Landscape of Novel Expressed Chimeric RNAs in Rheumatoid Arthritis

Frenkel‐Morgenstern

2022

Cells

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“…All these different disease-specific transcripts can generate the different phenotypes, which impact the normal protein interaction networks, switch pathways and change the regulatory landscape of the cells that can drive the disease development Abbreviations ARDS, acute respiratory distress syndrome; AS, alternative splicing; aTSS, alternative transcription start site; aTTS, alternative transcription termination site; DEGs, differentially expressed genes; IFN, interferon. [11][12][13][14][15]. Viral infections can also lead to widespread alternations of cellular splicing and altered transcripts, which are significantly associated with viral pathogenesis [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

The landscape of differential splicing and transcript alternations in severe COVID‐19 infection

et al. 2023

The FEBS Journal

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Viral infections can modulate the widespread alternations of cellular splicing, favouring viral replication within the host cells by overcoming host immune responses. However, how SARS‐CoV‐2 induces host cell differential splicing and affects the landscape of transcript alternation in severe COVID‐19 infection remains elusive. Understanding the differential splicing and transcript alternations in severe COVID‐19 infection may improve our molecular insights into the SARS‐CoV‐2 pathogenesis. In this study, we analysed the publicly available blood and lung transcriptome data of severe COVID‐19 patients, blood transcriptome data of recovered COVID‐19 patients at 12‐, 16‐ and 24‐week postinfection and healthy controls. We identified a significant transcript isoform switching in the individual blood and lung RNA‐seq data of severe COVID‐19‐infected patients and 25 common genes that alter their transcript isoform in both blood and lung samples. Altered transcripts show significant loss of the open reading frame, functional domains and switch from coding to noncoding transcript, impacting normal cellular functions. Furthermore, we identified the expression of several novel recurrent chimeric transcripts in the blood samples from severe COVID‐19 patients. Moreover, the analysis of the isoform switching into blood samples from recovered COVID‐19 patients highlights that there is no significant isoform switching in 16‐ and 24‐week postinfection, and the levels of expressed chimeric transcripts are reduced. This finding emphasizes that SARS‐CoV‐2 severe infection induces widespread splicing in the host cells, which could help the virus alter the host immune responses and facilitate the viral replication within the host and the efficient translation of viral proteins.

“…Chimeric transcripts are formed by the fusion of the exon/intron from two separate genes [ 22 ]. The generation of chimeric transcripts was found to be functionally involved with the development of several diseases [ 23 , 24 ]. Further, the appearance of chimeric transcripts in the cell is thought to be associated with the generation of phenotypic plasticity that helps the cell’s survival in response to specific stress [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

The Landscape of Expressed Chimeric Transcripts in the Blood of Severe COVID-19 Infected Patients

et al. 2023

Viruses

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The ongoing COVID-19 pandemic caused by SARS-CoV-2 infections has quickly developed into a global public health threat. COVID-19 patients show distinct clinical features, and in some cases, during the severe stage of the condition, the disease severity leads to an acute respiratory disorder. In spite of several pieces of research in this area, the molecular mechanisms behind the development of disease severity are still not clearly understood. Recent studies demonstrated that SARS-CoV-2 alters the host cell splicing and transcriptional response to overcome the host immune response that provides the virus with favorable conditions to replicate efficiently within the host cells. In several disease conditions, aberrant splicing could lead to the development of novel chimeric transcripts that could promote the functional alternations of the cell. As severe SARS-CoV-2 infection was reported to cause abnormal splicing in the infected cells, we could expect the generation and expression of novel chimeric transcripts. However, no study so far has attempted to check whether novel chimeric transcripts are expressed in severe SARS-CoV-2 infections. In this study, we analyzed several publicly available blood transcriptome datasets of severe COVID-19, mild COVID-19, other severe respiratory viral infected patients, and healthy individuals. We identified 424 severe COVID-19 -specific chimeric transcripts, 42 of which were recurrent. Further, we detected 189 chimeric transcripts common to severe COVID-19 and multiple severe respiratory viral infections. Pathway and gene enrichment analysis of the parental genes of these two subsets of chimeric transcripts reveals that these are potentially involved in immune-related processes, interferon signaling, and inflammatory responses, which signify their potential association with immune dysfunction leading to the development of disease severity. Our study provides the first detailed expression landscape of chimeric transcripts in severe COVID-19 and other severe respiratory viral infections.