Increased RNA editing in maternal immune activation model of neurodevelopmental disease

Tsivion-Visbord, Hadas; Kopel, Eli; Feiglin, Ariel; Sofer, Tamar; Barzilay, Ran; Ben‐Zur, Tali; Yaron, Orly; Offen, Daniel; Levanon, Erez Y.

doi:10.1038/s41467-020-19048-6

Cited by 33 publications

(29 citation statements)

References 101 publications

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“…simulating viral infection) in gestation leads to behavioural and cognitive dysfunctions relevant to schizophrenia in the offspring. 15 Gene expression changes in foetal brains following polyI:C administration were extracted from a published dataset. 15 In this study, we used the data from the study by Tsivion-Visbord et al for several reasons.…”

Section: Methodsmentioning

confidence: 99%

“… 15 Gene expression changes in foetal brains following polyI:C administration were extracted from a published dataset. 15 In this study, we used the data from the study by Tsivion-Visbord et al for several reasons. First, transcriptomic profiling through RNA sequencing provides comprehensive information on gene expression changes in the foetal brain.…”

Section: Methodsmentioning

confidence: 99%

“… 14 For example, offspring from mice exposed to polyinosinic:polycytidylic acid (polyI:C), a synthetic double-stranded RNA molecule that mimics viral infection, show pathological neurochemical and behavioural phenotypes that are characteristic of schizophrenia. 14 , 15 …”

Section: Introductionmentioning

confidence: 99%

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Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

Handunnetthi

Hamley

Knight

2021

Brain Communications

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Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Maternal immune activation by infections during pregnancy is hypothesized to be a key environmental risk factor. However, little is known about how maternal immune activation contributes to schizophrenia pathogenesis. In this study, we investigated if maternal immune activation influences the expression of genes associated with schizophrenia in foetal mouse brains. We found that two sets of schizophrenia genes were downregulated more than expected by chance in the foetal mouse brain following maternal immune activation, namely those genes associated with schizophrenia through genome-wide association study (fold change = 1.93, false discovery rate = 4 × 10−4) and downregulated genes in adult schizophrenia brains (fold change = 1.51, false discovery rate = 4 × 10−10). We found that these genes mapped to key biological processes, such as neuronal cell adhesion. We also identified cortical excitatory neurons and inhibitory interneurons as the most vulnerable cell types to the deleterious effects of this interaction. Subsequently, we used gene expression information from herpes simplex virus 1 infection of neuronal precursor cells as orthogonal evidence to support our findings and to demonstrate that schizophrenia-associated cell adhesion genes, PCDHA2, PCDHA3 and PCDHA5, were downregulated following herpes simplex virus 1 infection. Collectively, our results provide novel evidence for a link between genetic and environmental risk factors in schizophrenia pathogenesis. These findings carry important implications for early preventative strategies in schizophrenia.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

Handunnetthi

Hamley

Knight

2021

Brain Communications

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“…Interestingly, in mammals, ADAR expression can be stimulated by interferon (IFN) activity (Patterson and Samuel, 1995 ), and at the same time, ADAR can suppress IFN signaling (Hartner et al, 2009 ), suggesting a negative feedback loop. In a mouse model of viral infection that recapitulates ASD-associated behavioral changes, ADAR activity is increased, possibly due to IFN-induced ADAR expression (Tsivion-Visbord et al, 2020 ). As a consequence, the levels of RNA editing are increased in transcripts coding for proteins involved in neuronal development, metabolism, and the immune response.…”

Section: Malfunction Of Rna Binding Proteins and Associated Diseasesmentioning

confidence: 99%

“…As a consequence, the levels of RNA editing are increased in transcripts coding for proteins involved in neuronal development, metabolism, and the immune response. FLN- α and FLN- β were among the identified ADAR targets with altered levels of editing (Tsivion-Visbord et al, 2020 ). As discussed before, an interesting model is that dysregulation of editing in FLN- α and FLN- β could lead to changes in neuronal wiring, which in turn could be the cause of the observed behavioral changes.…”

Section: Malfunction Of Rna Binding Proteins and Associated Diseasesmentioning

confidence: 99%

The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

Landínez-Macías

Urwyler

2021

Front. Mol. Neurosci.

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Neuronal morphogenesis, integration into circuits, and remodeling of synaptic connections occur in temporally and spatially defined steps. Accordingly, the expression of proteins and specific protein isoforms that contribute to these processes must be controlled quantitatively in time and space. A wide variety of post-transcriptional regulatory mechanisms, which act on pre-mRNA and mRNA molecules contribute to this control. They are thereby critically involved in physiological and pathophysiological nervous system development, function, and maintenance. Here, we review recent findings on how mRNA metabolism contributes to neuronal development, from neural stem cell maintenance to synapse specification, with a particular focus on axon growth, guidance, branching, and synapse formation. We emphasize the role of RNA-binding proteins, and highlight their emerging roles in the poorly understood molecular processes of RNA editing, alternative polyadenylation, and temporal control of splicing, while also discussing alternative splicing, RNA localization, and local translation. We illustrate with the example of the evolutionary conserved Musashi protein family how individual RNA-binding proteins are, on the one hand, acting in different processes of RNA metabolism, and, on the other hand, impacting multiple steps in neuronal development and circuit formation. Finally, we provide links to diseases that have been associated with the malfunction of RNA-binding proteins and disrupted post-transcriptional regulation.

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Histone mRNA polyadenylation‐mediated inflammation underlies various virus infections and cancers

Guo

Zhu

et al. 2023

Journal of Medical Virology

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The mechanistic understanding of virus infection and inflammation in many diseases is incomplete. Normally, messenger RNA (mRNA) tails of replication‐dependent histones (RDH) that safeguard naked nuclear DNAs are protected by a specialized stem‐loop instead of polyadenylation. Here, we showed that infection by various RNA viruses (including severe acute respiratory syndrome coronavirus 2) induced aberrant polyadenylation of RDH mRNAs (pARDH) that resulted in inflammation or cellular senescence, based on which we constructed a pARDH inflammation score (pARIS). We further investigated pARIS elevation in various disease conditions, including different types of virus infection, cancer, and cellular senescence. Notably, we found that pARIS was positively correlated with coronavirus disease 2019 severity in specific immune cell types. We also detected a subset of HIV‐1 elite controllers characterized by pARDH “flipping” potentially mediated by HuR. Importantly, pARIS was positively associated with transcription of endogenous retrovirus but negatively associated with most immune cell infiltration in tumors of various cancer types. Finally, we identified and experimentally verified two pARIS regulators, ADAR1 and ZKSCAN1, which was first linked to inflammation. The ZKSCAN1 was known as a transcription factor but instead was shown to regulate pARIS as a novel RNA binding protein. Both regulators were upregulated under most infection and inflammation conditions. In conclusion, we unraveled a potential antiviral mechanism underlying various types of virus infections and cancers.

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Increased RNA editing in maternal immune activation model of neurodevelopmental disease

Cited by 33 publications

References 101 publications

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

Histone mRNA polyadenylation‐mediated inflammation underlies various virus infections and cancers

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