The RNA exosome maintains cellular RNA homeostasis by controlling transcript abundance in the brain
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PROVIDER: PRJNA1176667 | ENA |
REPOSITORIES: ENA
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Project description:Intracellular ribonucleases (RNases) are essential in all aspects of RNA metabolism, including maintaining accurate RNA levels. Inherited mutations in genes encoding ubiquitous RNases are associated with human diseases, primarily affecting the nervous system. Recessive mutations in genes encoding an evolutionarily conserved RNase complex, the RNA exosome, lead to syndromic neurodevelopmental disorders characterized by progressive neurodegeneration, such as Pontocerebellar Hypoplasia Type 1b (PCH1b). We establish a CRISPR/Cas9-engineered Drosophila model of PCH1b to study cell-type-specific post-transcriptional regulatory functions of the nuclear RNA exosome complex within fly head tissue. Here, we report that pathogenic RNA exosome mutations alter activity of the complex, causing widespread dysregulation of brain-enriched cellular transcriptomes, including rRNA processing defects—resulting in tissue-specific, progressive neurodegenerative effects in flies. These findings provide a comprehensive understanding of RNA exosome function within a developed animal brain and underscore the critical role of post-transcriptional regulatory machinery in maintaining cellular RNA homeostasis within the brain.
2024-11-01 | GSE280166 | GEO
Project description:Eukaryotic genomes produce a large variety of RNAs some of which are present in the chromatin and may affect important processes such as chromatin packaging and gene expression. Little is known about the role of the RNA exosome in the regulation of such chromatin-associated RNAs (caRNAs). The project aims at 1) identifying caRNAs produced from unique and repetitive sequences in the genome of Drosophila melanogaster S2 cells, and 2) characterize the role of the RNA exosome in controlling caRNA levels. To answer these questions, we have used RNA interference to knock down the exosome catalytic subunits RRP6 and DIS3 (individually or simultaneously) and we have analyzed the effects of the depletions on the chromatin-associated transcriptome by sequencing RNAs purified from a chromatin fraction isolated from S2 cells.
2025-01-01 | GSE222260 | GEO
Project description:Pervasive transcription of the human genome generates an abundance of RNAs that must be processed and degraded. The nuclear RNA exosome is the main RNA degradation machinery in the nucleus. However, nuclear exosome must be recruited to its substrates by targeting complexes, such as NEXT or PAXT. By proteomic analysis, we have identified additional subunits of PAXT, including many orthologs of MTREC found in S. pombe. In particular, we show that polyA polymerase gamma was associated with PAXT. Genome-wide mapping of the binding sites of ZFC3H1, RBM26 and PAPgamma, showed that PAXT is recruited to the TSS of hundreds of genes. Loss of ZFC3H1 abolished recruitment of PAXT subunits including PAPgamma to TSSs and concomitantly increased the abundance of PROMPTs at the same sites. Moreover, PAPgamma polyadenylated PROMPTs and modulated their stability. Our results thus provide key insights into the direct targeting and degradation of PROMPT ncRNAs by PAXT, at their genomic sites and depending on polyadenylation of RNAs.
2023-10-02 | GSE189157 | GEO
Project description:Nuclear 3’ to 5’ nuclease RNA exosome plays a key role in quality control and processing of multiple protein-coding and non-coding transcripts made by RNA polymerase II. A mechanistic understanding of exosome function remains a challenge given the large number of RNA species and intervening RNA processing factors. Here we analysed changes in the poly(A)+ RNA proteins interactome provoked by mutations in three distinct subunits of the nuclear RNA exosome. Our data demonstrate a functional connection between Rrp6 and Mtl1 in controlling processing and levels of multiple protein-coding and non-coding transcripts. Furthermore, we show that exosome mutants accumulate components of U1 and U2 snRNPs and show depletion of NTC components from RNA suggesting that the stage prior to the activation of the spliceosome represents a critical quality control step. We have also identified potential new RNA binding factors involved in exosome regulation, including a zinc-finger protein called Mub1 that controls levels of selected transcripts encoding for proteins implicated in stress response. Collectively, our data have provided a global view of RNA metabolism alterations in exosome deficient cells and revealed RNA binding proteins that may act as novel exosome cofactors.
2020-04-17 | GSE148799 | GEO
Project description:The exosome degrades chromatin-associated RNAs genome-wide and maintains chromatin homeostasis (RNA-Seq)
| PRJNA918705 | ENA
Project description:The exosome degrades chromatin-associated RNAs genome-wide and maintains chromatin homeostasis
| PRJNA918701 | ENA
Project description:Gene expression programs change during cellular transitions. It is well established that a network of transcription factors and chromatin modifiers regulate RNA levels during embryonic stem cell (ESC) differentiation, but the full impact of post-transcriptional processes remains elusive. While cytoplasmic RNA turnover mechanisms have been implicated in differentiation, the contribution of nuclear RNA decay has not been investigated. Here, we differentiate mouse ESCs, depleted for the ribonucleolytic RNA exosome, into embryoid bodies to determine to which degree RNA abundance in the two states can be attributed to changes in transcription vs. RNA decay by the exosome. As a general observation, we find that exosome depletion mainly leads to the stabilization of RNAs from lowly transcribed loci, including several protein-coding genes. In particular, transcripts that are differentially expressed between states tend to be more exosome sensitive in the state where expression is low. We conclude that the RNA exosome contributes to down-regulation of transcripts with disparate expression, often in conjunction with transcriptional down-regulation.
2018-08-31 | GSE115714 | GEO
Project description:Gene expression programs change during cellular transitions. It is well established that a network of transcription factors and chromatin modifiers regulate RNA levels during embryonic stem cell (ESC) differentiation, but the full impact of post-transcriptional processes remains elusive. While cytoplasmic RNA turnover mechanisms have been implicated in differentiation, the contribution of nuclear RNA decay has not been investigated. Here, we differentiate mouse ESCs, depleted for the ribonucleolytic RNA exosome, into embryoid bodies to determine to which degree RNA abundance in the two states can be attributed to changes in transcription vs. RNA decay by the exosome. As a general observation, we find that exosome depletion mainly leads to the stabilization of RNAs from lowly transcribed loci, including several protein-coding genes. Depletion of the nuclear exosome cofactor RBM7 leads to similar effects. In particular, transcripts that are differentially expressed between states tend to be more exosome sensitive in the state where expression is low. We conclude that the RNA exosome contributes to down-regulation of transcripts with disparate expression, often in conjunction with transcriptional down-regulation.
2018-08-31 | GSE118054 | GEO
Project description:Large fractions of genomes are expressed in most eukaryotic cells, generating a diverse repertoire of protein-coding and non-coding transcripts. With such complexity, and as the number of mRNA molecules per cell are often low, it is clear that errors anywhere in the gene expression process could have profound consequences on cellular functions. The exosome is a conserved RNA degradation machine that plays a fundamental role in monitoring the quality of gene expression in the nucleus. The current view is that the nuclear exosome constantly scrutinizes transcription and contributes to post-transcriptional turnover of faulty mRNAs. Yet, how nuclear RNA surveillance by the exosome is coordinated with transcription is still unknown. Here we show that the exosome can directly target the transcription machinery by terminating transcription events associated with paused and backtracked RNA polymerase II (RNAPII), contrary to the notion that the exosome acts exclusively on RNAs that have been released by RNAPII. Our data support a mechanism by which RNAPII backtracking provides a free RNA 3' end for the core exosome, resulting in transcription termination with the concomitant degradation of the associated transcript. These findings uncover a mechanism of co-transcriptional RNA surveillance whereby termination of transcription by the exosome prevents aberrant read-through RNAs and transcriptional interference at neighboring genes.
2014-09-20 | E-MTAB-2237 | biostudies-arrayexpress
Project description:PAP-gamma associates with PAXT nuclear exosome to control the abundance of PROMPT ncRNAs
| PRJNA781729 | ENA