The dsRNA-enriched neural transcriptome drives neuroinflammation [neurons]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE214941 | GEO | 2023/10/20
REPOSITORIES: GEO
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Project description:Alternative polyadenylation is a widespread mechanism involving about half of the expressed genes, resulting in varying lengths of the 3' UTR and changes of the post-transcriptional processing, localization, miRNA targeting and stability of mRNAs. During neuronal differentiation a variety of mRNAs change the length of their 3' UTR, promoting the longer version of the transcripts. Little is known about polyA+ site usage during differentiation of mammalian neural progenitors. Here we exploit a model of adherent neural stem (ANS) cells, which homogeneously and efficiently differentiate into GABAergic neurons. RNAseq data shows a global trend towards lengthening of the 3’ UTRs during differentiation. Enriched expression of the long 3’ UTR variants of Pes1 and Gng2 was detected in areas of cortical and subcortical neuronal differentiation, respectively, in the mouse brain by two-probes FISH analyses. In Drosophila the choice of polyA+ site has been shown to be regulated by the RNA-binding protein Elav, which inhibits polyadenylation at proximal sites while interacting with paused Pol-II promoters. Among the coding genes upregulated during differentiation of ANS cells we found Elavl3, a neural-specific RNA-binding protein homologous to Drosophila Elav. The silencing of Elavl3 in ANS cells resulted in impaired elongation of the 3’UTR length and delayed neuronal differentiation. These results indicate that choice of the polyA+ site and lengthening of 3’ UTRs is a possible additional mechanism of posttranscriptional RNA modification involved in neuronal differentiation.
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Project description:The 3' untranslated regions (3' UTRs) of mRNAs contain cis-acting elements for posttranscriptional regulation of gene expression. Here, we report that mouse genes tend to express mRNAs with longer 3' UTRs as embryonic development progresses. This global regulation is controlled by alternative polyadenylation and coordinates with initiation of organogenesis and aspects of embryonic development, including morphogenesis, differentiation, and proliferation. Using myogenesis of C2C12 myoblast cells as a model, we recapitulated this process in vitro and found that 3' UTR lengthening is likely caused by weakening of mRNA polyadenylation activity. Because alternative 3' UTR sequences are typically longer and have higher AU content than constitutive ones, our results suggest that lengthening of 3' UTR can significantly augment posttranscriptional control of gene expression during embryonic development, such as microRNA-mediated regulation.
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Project description:PurposeCornea, the outermost transparent layer of the eye, is the first line of defense against external threats. Following injury, the wound healing response is crucial to corneal repair and regeneration, yet its underlying mechanism is poorly understood. Our study was designed to investigate the role of dsRNA and its regulatory network in corneal wound healing.MethodsA corneal wound healing model was established via the surgical removal of half of the corneal surface and adjoining limbus. RNase III was then used to clarify the role of dsRNA in corneal wound closure and RNA-seq was performed to investigate the mechanism of dsRNA in the healing process. Related gene expression was assessed using immunofluorescence staining, qPCR, and Western blot. Flow cytometry and scratch assay were used to analyze the proliferation and migration of limbal stem/progenitor cells (LSCs) in vitro and functional analysis of the target genes was completed using the corneal wound healing model.ResultsCorneal wound healing was delayed and impaired when the dsRNAs were removed or damaged following RNase III digestion. The dsRNAs released following corneal damage activate type I interferon (IFN-I) signaling, primarily IFNβ, via the corneal epithelium and neutralizing IFNβ or blocking IFN-I signaling delays corneal wound closure. Moreover, our data identified MMP13 as a downstream effector of IFNβ where its expression promotes LSC proliferation and enhances corneal epithelial reconstruction in vivo.ConclusionsThe dsRNA induced IFNβ-MMP13 axis plays a key role in corneal wound healing.
| S-EPMC8822365 | biostudies-literature