Role of RNA-binding protein PTBP1 in viral RNA nucleocytoplasmic transport and in HSV-1 infection
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE252422 | GEO | 2026/01/01
REPOSITORIES: GEO
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Project description:Polypyrimidine tract-binding protein 1 (PTBP1) is an RNA-binding protein (RBP) that plays an instrumental role in regulating alternative splicing events by manipulating RNA folding. Here we report a novel role of PTBP1 in heparan sulfate (HS) biosynthesis. Specifically, we found that genetic ablation of PTBP1 resulted in loss of HS3ST3A1 and HS3ST3B1 (also known as 3OST3A1 and 3OST3B1, respectively) expression. Both the HS3ST3A1 and HS3ST3B1 genes, which encode heparan sulfate -glucosamine 3-O-sulfotransferases for heparan sulfate modification of proteoglycans (HSPGs), are unique in that each pre-mRNA is composed of 2 exons separated by an extraordinarily long intron. Analyses of global iCLIP-seq and CRIC-seq revealed that the intron region of HS3ST3A1/HS3ST3B1 pre-mRNAs interacted with the PTBP1 dimer, creating contacts to impact splicing events. Ectopic expression of WT, but not a dimerization defective mutant (C23S) of PTBP1, restored functional 3OST3 expression. Cell-surface HSPGs are the most abundant proteoglycans that can act as co-receptors modulating cytokine activities as well as for viruses to attach and to enter cells. We showed that loss of 3OST3 expression markedly reduced HSV-1 infection and viral spreading. This study demonstrates that PTBP1 mediates 3OST3 expression for HS biosynthesis and plays a role in HSV-1 infection.
2025-11-24 | GSE297152 | GEO
Project description:Role of RNA-binding protein PTBP1 in viral RNA nucleocytoplasmic transport and in HSV-1 infection
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Project description:We report a HSV-1 encoded miRNA present during lytic infection that influences replication efficiency in a tissue culture model. miRNAs were identified using high-throughput sequencing of HSV-1 infected epithelial cells. Functional assays were performed by mutating the miRNA coding region and testing grow of the mutant in vitro. Construction of a miRNA library and sequencing to reveal novel viral miRNAs from lytically infected cells
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Project description:Herpes simplex virus 1 (HSV-1) switches between lytic and latent infections in neurons, yet the switch mechanisms remain obscure. Here we identify forkhead box (FOX) family proteins that can strongly activate or repress HSV-1 replication particularly in neuronal cells. Expression of activating FOX genes (Foxa, Foxc, Foxe, Foxf) is ordinarily low and expression of repressive FOX genes (Foxk) is high in neurons. Lytic HSV-1 infection and other stresses can increase activating FOX gene expression. Such overexpression or knockout of endogenous FOXK1 promotes reactivation from latency. These FOX proteins broadly associate with the viral genome and regulate viral gene transcription through epigenetic modulators. FOXF1 associates with histone acetyltransferases CBP and P300 to open viral chromatin. FOXK1 collaborates with SIN3A, a known cofactor of histone deacetylation, and MAX to suppress HSV-1 replication and antagonize activating FOX proteins. Thus, HSV-1 uses FOX family members with opposing effects to regulate the lytic-latent balance.
2026-01-09 | GSE299792 | GEO
Project description:Epigenetic modulation of herpes simplex virus (HSV) immediate early (IE) genes is a critical regulatory parameter governing lytic infection, latency, and viral reactivation. Multiple factors, including epigenetic complexes associated with the cellular transcriptional coactivator HCF-1, modulate the state of HSV-1 chromatin. As an approach to identify novel epigenetic factors that regulate the initial stage of HSV-1 infection, an epigenetic chemical probe library was screened for their impact on viral IE gene expression. This screen identified several epigenetic inhibitors that modulated IE expression. Notably, UNC0379, an inhibitor of the histone H4K20 mono-methyltransferase SETD8, potently repressed HSV-1 infection in vitro and in vivo. Furthermore, SETD8 inhibition suppressed HSV-1 reactivation in a mouse ganglia explant model. Importantly, these results correlated with enhanced heterochromatin suppression and decreased accessibility of HSV-1 chromatin. Reduced IE transcription was concomitant with disruption in recruitment of HCF-1 and RNA polymerase II (RNAPII). These results are consistent with the established roles of SETD8 in promoting chromatin accessibility through H4K20me1 deposition and regulating transcriptional elongation, suggesting that SETD8 may facilitate multiple steps in regulation of HSV-1 IE gene expression.
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Project description:Epigenetic modulation of herpes simplex virus (HSV) immediate early (IE) genes is a critical regulatory parameter governing lytic infection, latency, and viral reactivation. Multiple factors, including epigenetic complexes associated with the cellular transcriptional coactivator HCF-1, modulate the state of HSV-1 chromatin. As an approach to identify novel epigenetic factors that regulate the initial stage of HSV-1 infection, an epigenetic chemical probe library was screened for their impact on viral IE gene expression. This screen identified several epigenetic inhibitors that modulated IE expression. Notably, UNC0379, an inhibitor of the histone H4K20 mono-methyltransferase SETD8, potently repressed HSV-1 infection in vitro and in vivo. Furthermore, SETD8 inhibition suppressed HSV-1 reactivation in a mouse ganglia explant model. Importantly, these results correlated with enhanced heterochromatin suppression and decreased accessibility of HSV-1 chromatin. Reduced IE transcription was concomitant with disruption in recruitment of HCF-1 and RNA polymerase II (RNAPII). These results are consistent with the established roles of SETD8 in promoting chromatin accessibility through H4K20me1 deposition and regulating transcriptional elongation, suggesting that SETD8 may facilitate multiple steps in regulation of HSV-1 IE gene expression.
2025-11-10 | GSE302606 | GEO
Project description:Herpes simplex virus replicates and forms progeny in the nucleus where it must overcome host chromatin to establish a successful infection. During lytic infection, newly formed viral capsids navigate through heterochromatin channels at the nuclear periphery to egress out of the nucleus. In uninfected cells, specific histone marks such as trimethylation on histone H3 lysine 27 (H3K27me3) and the histone variant macroH2A1 delineate heterochromatin regions, or repressed chromatin, that are predominantly located in the nuclear periphery. We examined these markers during HSV-1 lytic infection in primary cells and discovered a striking increase in the levels of macroH2A1 and H3K27me3. Here, we demonstrate that the loss of macroH2A1 results in significantly lower viral titers but does not impair viral transcription, protein production, or replication. By inhibiting the deposition of H3K27me3 by EZH2, we further show that reduction of H3K27me3 also leads to a significant decrease in viral titers. Through chromatin profiling via Cleavage Under Targets and tagmentation (CUT&Tag) of macroH2A1 and H3K27me3, we define the specific chromatin regions that change dynamically during HSV-1 lytic infection and show that regions with increased macroH2A1 and H3K27me3 correlate with decreased host transcription as measured by RNA-seq. Furthermore, we find by electron microscopy that loss of macroH2A1 results in reduced heterochromatin at the nuclear periphery and significantly more viral capsids trapped in the nuclear compartment. Using both high and low shedding clinical isolates of HSV-1, we similarly find that HSV-1 titers are significantly reduced in the absence of macroH2A1. Our work demonstrates that HSV-1 takes advantage of the dynamic nature of host heterochromatin formation during infection for efficient viral egress from the nuclear compartment.
2023-07-01 | GSE209632 | GEO
Project description:Herpes simplex virus replicates and forms progeny in the nucleus where it must overcome host chromatin to establish a successful infection. During lytic infection, newly formed viral capsids navigate through heterochromatin channels at the nuclear periphery to egress out of the nucleus. In uninfected cells, specific histone marks such as trimethylation on histone H3 lysine 27 (H3K27me3) and the histone variant macroH2A1 delineate heterochromatin regions, or repressed chromatin, that are predominantly located in the nuclear periphery. We examined these markers during HSV-1 lytic infection in primary cells and discovered a striking increase in the levels of macroH2A1 and H3K27me3. Here, we demonstrate that the loss of macroH2A1 results in significantly lower viral titers but does not impair viral transcription, protein production, or replication. By inhibiting the deposition of H3K27me3 by EZH2, we further show that reduction of H3K27me3 also leads to a significant decrease in viral titers. Through chromatin profiling via Cleavage Under Targets and tagmentation (CUT&Tag) of macroH2A1 and H3K27me3, we define the specific chromatin regions that change dynamically during HSV-1 lytic infection and show that regions with increased macroH2A1 and H3K27me3 correlate with decreased host transcription as measured by RNA-seq. Furthermore, we find by electron microscopy that loss of macroH2A1 results in reduced heterochromatin at the nuclear periphery and significantly more viral capsids trapped in the nuclear compartment. Using both high and low shedding clinical isolates of HSV-1, we similarly find that HSV-1 titers are significantly reduced in the absence of macroH2A1. Our work demonstrates that HSV-1 takes advantage of the dynamic nature of host heterochromatin formation during infection for efficient viral egress from the nuclear compartment.
2023-07-01 | GSE208127 | GEO
Project description:Neuronal reprogramming of astrocytes poses a promising therapeutic approach to replace degenerating cells with newly converted neurons. Recent studies reported depletion of polyprimidine tract binding protein PTBP1, a repressor of neuronal alternative splicing, could induce astrocyte to neuron conversion and rescue functional deficits in models of neurodegenerative disease, while others disputed the astrocytic origin of converted neurons. Mechanistic understanding of the conversion, or the lack thereof, requires investigating the transcriptomic effects of Ptbp1 loss of function in mature astrocytes on RNA splicing, in conjunction with lineage tracing, which have not yet been examined. Here, we used genetic depletion of Ptbp1 in adult Aldh1l1-Cre/ERT2 reporter mice to determine whether lineage traced Ptbp1 knockout astrocytes exhibited RNA splicing alterations underlying potential neuronal transdifferentiation. Our analysis employed an alternative genetic Ptbp1 knockout mouse model and an extended 12-week window of Ptbp1 knockout to match previous reports of positive conversion. We found no widespread induction of neuronal identity, despite detecting a minuscule fraction of Cre-positive cells with neuronal transcriptomic features following Ptbp1 deletion. Importantly, PTBP1 depletion in mature astrocytes induces splicing alternations unlike neuronal features of alternative splicing. These findings highlight the challenge of targeting astrocytes for neuronal conversion via Ptbp1 knockout and underscore the importance of cellular gene expression profiling and genetic lineage tracing for in vivo studies of cell type conversion.
2025-08-06 | GSE294763 | GEO
Project description:Neuronal reprogramming of astrocytes poses a promising therapeutic approach to replace degenerating cells with newly converted neurons. Recent studies reported depletion of polyprimidine tract binding protein PTBP1, a repressor of neuronal alternative splicing, could induce astrocyte to neuron conversion and rescue functional deficits in models of neurodegenerative disease, while others disputed the astrocytic origin of converted neurons. Mechanistic understanding of the conversion, or the lack thereof, requires investigating the transcriptomic effects of Ptbp1 loss of function in mature astrocytes on RNA splicing, in conjunction with lineage tracing, which have not yet been examined. Here, we used genetic depletion of Ptbp1 in adult Aldh1l1-Cre/ERT2 reporter mice to determine whether lineage traced Ptbp1 knockout astrocytes exhibited RNA splicing alterations underlying potential neuronal transdifferentiation. Our analysis employed an alternative genetic Ptbp1 knockout mouse model and an extended 12-week window of Ptbp1 knockout to match previous reports of positive conversion. We found no widespread induction of neuronal identity, despite detecting a minuscule fraction of Cre-positive cells with neuronal transcriptomic features following Ptbp1 deletion. Importantly, PTBP1 depletion in mature astrocytes induces splicing alternations unlike neuronal features of alternative splicing. These findings highlight the challenge of targeting astrocytes for neuronal conversion via Ptbp1 knockout and underscore the importance of cellular gene expression profiling and genetic lineage tracing for in vivo studies of cell type conversion.
2025-08-06 | GSE294768 | GEO