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Dis3l2-Mediated RNA Surveillance and Extracellular Vesicle Packaging Prevent Innate Immune Activation by Aberrant Cellular RNAs [miRNA-Seq]

ABSTRACT: Although most efforts to understand the functions of RNAs packaged in extracellular vesicles (EVs) have focused on mRNAs and miRNAs, recent studies using less-biased sequencing techniques have revealed that tRNAs and other noncoding RNAs (ncRNAs) are far more abundant. However, the extent to which EV ncRNAs resemble overall cellular RNAs and the benefits to host cells of packaging them into EVs remain unknown. Here, we purified EVs from the culture media of mouse and human cells and characterized their RNA components using high throughput sequencing and Northern blotting. We report that EVs are enriched for numerous aberrant ncRNAs, many of which contain oligouridine tails, a modification associated with degradation by Dis3l2, a cytosolic exoribonuclease that degrades defective structured ncRNAs. Both the numbers of EVs released and the fractions of tailed RNAs in EVs increase on Dis3l2 depletion, indicating that packaging of aberrant ncRNAs into EVs occurs in competition with Dis3l2 decay. Upregulation of multiple type I interferon stimulated genes (ISGs) occurs on Dis3l2 depletion, and cells treated with a neutral sphingomyelinase inhibitor that reduces exosome biogenesis also show moderate ISG upregulation, an effect that is enhanced in Dis3l2-depleted cells and accompanied by the accumulation of aberrant ncRNAs in cellular RNA. Thus, Dis3l2 degradation and packaging of aberrant RNAs into vesicles may prevent these RNAs from activating innate immune sensors and triggering an interferon response.

ORGANISM(S): Mus musculus

PROVIDER: GSE307560 | GEO | 2025/12/16

REPOSITORIES: GEO

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Project description:Mutations in the 3’-5’ exonuclease DIS3L2 are associated with Perlman syndrome and hypersusceptibility to Wilms’ tumorigenesis. Previously, we found that Dis3l2 specifically recognizes and degrades uridylated pre-let-7 microRNA. However, the widespread relevance of Dis3l2-mediated decay of uridylated substrates remains unknown. Here we applied an unbiased RNA immunoprecipitation strategy to identify Dis3l2 targets in mouse embryonic stem cells. The disease-associated long noncoding RNA (lncRNA) Rmrp, 7SL, as well as several other Pol III-transcribed noncoding RNAs (ncRNAs) were among the most highly enriched Dis3l2-bound RNAs. 3’-uridylated Rmrp, 7SL, and snRNA species were highly stabilized in the cytoplasm of Dis3l2-depleted cells. Deep sequencing analysis of Rmrp 3’ ends revealed extensive oligouridylation mainly on transcripts with imprecise ends. We implicate the TUTases Zcchc6/11 in the uridylation of these ncRNAs, and biochemical reconstitution assays demonstrate the sufficiency of TUTase-Dis3l2 for Rmrp decay. This establishes Dis3l2-Mediated Decay (DMD) as a quality control pathway that eliminates aberrant ncRNAs.obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts. We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential. Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation. Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences. Lysine 4 and lysine 9 trimethylation marks imprinting control regions. Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms. This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations.

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Dis3l2-Mediated RNA Surveillance and Extracellular Vesicle Packaging Prevent Innate Immune Activation by Aberrant Cellular RNAs [miRNA-Seq]

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