RNA Splicing and Disease: Animal Models to Therapies

Montes, Matías; Sanford, Brianne; Comiskey, Daniel F.; Chandler, Dawn S.

doi:10.1016/j.tig.2018.10.002

Cited by 174 publications

(127 citation statements)

References 158 publications

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“…In this study, we used the transcriptome data of different peripheral immune organs to reveal that alternative splicing events were significantly increased in response to PRRSV infection, especially the increase in the frequency of SE type. Previous reports have revealed that SE was always the most frequent alternative splicing event in a large number of animal studies [20,40]. It has been reported that the splicing level of host RNA will be changed when the virus invades the organism, which may be caused by the direct effect of the virus and the role of the immune response of the organism [4].…”

Section: Discussionmentioning

confidence: 97%

Global Analysis of Alternative Splicing Difference in Peripheral Immune Organs between Tongcheng Pigs and Large White Pigs Artificially Infected with PRRSV In Vivo

Zhang

Xue

Hang

et al. 2020

BioMed Research International

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Alternative splicing (AS) plays a significant role in regulating gene expression at the transcriptional level in eukaryotes. Flexibility and diversity of transcriptome and proteome can be significantly increased through alternative splicing of genes. In the present study, transcriptome data of peripheral immune organs including spleen and inguinal lymph nodes (ILN) were used to identify AS difference between PRRSV-resistant Tongcheng (TC) pigs and PRRSV-susceptible Large White (LW) pigs artificially infected with porcine reproductive and respiratory syndrome virus (PRRSV) in vivo. The results showed that PRRSV infection induced global alternative splicing events (ASEs) with different modes. Among them, 373 genes and 595 genes in the spleen and ILN of TC pigs, while 458 genes and 560 genes in the spleen and ILN of LW pigs had significantly differential ASEs. Alternative splicing was subject to tissue-specific and lineage-specific regulation in response to PRRSV infection. Enriched GO terms and pathways showed that genes with differential ASEs played important roles in transcriptional regulation, immune response, metabolism, and apoptosis. Furthermore, a splicing factor associated with apoptosis, SRSF4, was significantly upregulated in LW pigs. Functional analysis on apoptosis associated genes was validated by RT-PCR and DNA sequencing. These findings revealed different response to PRRSV between PRRSV-resistant TC pigs and PRRSV-susceptible LW pigs at the level of alternative splicing, suggesting the potential relationship between AS and disease resistance to PRRSV.

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Section: Discussionmentioning

confidence: 97%

Global Analysis of Alternative Splicing Difference in Peripheral Immune Organs between Tongcheng Pigs and Large White Pigs Artificially Infected with PRRSV In Vivo

Zhang

Xue

Hang

et al. 2020

BioMed Research International

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“…Cell-specific alternative splicing is essential for normal cell function, and ~30% of all disease-causing mutations are related to RNA splicing (Montes et al, 2019). Our studies reveal the cell-specific mechanisms that govern alternative splicing of a critical synaptic calcium ion channel gene and they shed light on chronic pathology that follows nerve injury.…”

Section: Discussionmentioning

confidence: 99%

Cell-specific exon methylation and CTCF binding in neurons regulates calcium ion channel splicing and function

Soto

Lipscombe

2019

Preprint

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Cell-specific alternative splicing modulates myriad cell functions and this process is disrupted in disease. The mechanisms governing alternative splicing are known for relatively few genes and typically focus on RNA splicing factors. In sensory neurons, cell-specific alternative splicing of the presynaptic voltage-gated calcium channel Cacna1b gene modulates opioid sensitivity. How this splicing is regulated has remained unknown. We find that cell-specific exon DNA hypomethylation permits binding of CTCF, the master regulator of chromatin structure in mammals, which, in turn, controls splicing in noxious heat-sensing nociceptors.Hypomethylation of an alternative exon specifically in nociceptors allows for CTCF binding, and expression of CaV2.2 channels with increased opioid sensitivity. Following nerve injury, exon methylation is increased, and splicing is disrupted. Our studies define the molecular mechanisms of cell-specific alternative splicing of a functionally validated exon in normal and disease statesand reveal a potential target for the treatment of chronic pain.Highlights (each bullet not > 85 characters including spaces)• The molecular basis of cell-specific splicing of a synaptic calcium channel gene.• Splicing controlled by cell-specific exon hypomethylation and CTCF binding.• Peripheral nerve injury disrupts exon hypomethylation and splicing.• Targeted demethylation of exon by dCAS9-TET modifies alternative splicing.

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“…Alternative splicing (AS) of pre-mRNA is the differential processing of introns and exons to generate multiple transcript isoforms from individual genes, thereby increasing molecular diversity. However, when it is not properly executed, AS leads to mis-splicing, which may result in proteins with altered function and stability 1 . A number of splicing factors and other RNAbinding proteins (RBPs) are responsible for proper regulation of AS 2 , and growing evidence has implicated mis-splicing in a range of pathologies such as cancer 3 , muscular dystrophies 4 , autism 5,6 and neurodegenerative diseases 7 such as Alzheimer´s disease 8,9 , amyotrophic lateral sclerosis 10,11 and Huntington's disease [12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Huntington’s disease-specific mis-splicing captured by human-mouse intersect-RNA-seq unveils pathogenic effectors and reduced splicing factors

Elorza

Márquez

Cabrera

et al. 2020

Preprint

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Deregulated alternative splicing has been implicated in a wide range of pathologies. Deep RNAsequencing has revealed global mis-splicing signatures in multiple human diseases; however, for neurodegenerative diseases, these analyses are intrinsically hampered by neuronal loss and neuroinflammation in post-mortem brains. To infer splicing alterations relevant to Huntington's disease (HD) pathogenesis, here we performed intersect-RNA-seq analyses of human postmortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis are not yet present. Together with a human/mouse parallel motif scan analysis, this approach allowed us to identify the shared mis-splicing signature triggered by the HD-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked effector genes, whose aberrant splicing is associated with decreased protein levels in HD patients and mice. In summary, our intersect-RNA-seq approach unveiled the pathogenic contribution of mis-splicing to HD and could be readily applied to other neurodegenerative diseases for which bona fide animal models are available.

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RNA Splicing and Disease: Animal Models to Therapies

Cited by 174 publications

References 158 publications

Global Analysis of Alternative Splicing Difference in Peripheral Immune Organs between Tongcheng Pigs and Large White Pigs Artificially Infected with PRRSV In Vivo

Global Analysis of Alternative Splicing Difference in Peripheral Immune Organs between Tongcheng Pigs and Large White Pigs Artificially Infected with PRRSV In Vivo

Cell-specific exon methylation and CTCF binding in neurons regulates calcium ion channel splicing and function

Huntington’s disease-specific mis-splicing captured by human-mouse intersect-RNA-seq unveils pathogenic effectors and reduced splicing factors

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