Neural stem cells alter nucleocytoplasmic partitioning and accumulate nuclear polyadenylated transcripts during quiescence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA680360 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13120325.fastq.gz | Fastqsanger.gz | |||
| SRR13120326.fastq.gz | Fastqsanger.gz | |||
| SRR13120327.fastq.gz | Fastqsanger.gz | |||
| SRR13120328.fastq.gz | Fastqsanger.gz | |||
| SRR13120329.fastq.gz | Fastqsanger.gz |
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Project description:Quiescence is a cellular state characterized by reversible cell-cycle arrest and diminished biosynthetic activity that protects against environmental insults, replicative exhaustion and proliferation-induced mutations. Entry into and exit from this state controls development, maintenance and repair of tissues, plus in the adult central nervous system, generation of new neurons and thus cognition and mood. Cancer stem cells too can undergo quiescence, which confers them resistance to current therapies. Despite clinical relevance, quiescence lacks understanding and is defined functionally given lack of molecular markers. Inhibition of the Target of Rapamycin pathway is a common denominator of quiescence across species and cell types. This pathway integrates diverse signals towards control of metabolism and cytoskeleton, and lowered pathway activity in quiescence ensures decrease of the most resource-¬intensive cellular process of protein synthesis. Here, we combine Drosophila genetics and a mammalian model to show that altered nucleocytoplasmic partitioning and nuclear bias of a fraction of polyadenylated RNAs are novel evolutionarily conserved mechanisms of quiescence regulation. Altogether, these mechanisms contribute a new regulatory layer to inhibition of protein translation in quiescent cells, whilst likely priming them for quick reactivation in response to appropriate cues.
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Project description:The paired-end next-generation sequencing of all hTR versions of less than 200 nucleotides in length was used to analyze the 3’ end distribution of hTR associated to Flag-tagged versions of PABPN1, hTERT and Dyskerin. In total, we obtained 2,716,342, 3,152,013, and 3,077,395 hTR-specific reads for the PABPN1, hTERT, and Dyskerin purifications, respectively. We found that the majority of polyadenylated telomerase RNA recovered in the PABPN1, hTERT, and Dyskerin purifications had poly(A) tails starting immediately after the annotated hTR 3’ end. However, a greater proportion of poly(A) tails were found on genome-encoded 3’-extentions in the PABPN1-bound fraction compared to the population of hTR that was copurified with hTERT and DKC1: 15.5% for PABPN1, 6.9% for hTERT, and 6.5% for Dyskerin. Notably, the population of polyadenylated telomerase RNA recovered with PABPN1 was significantly different in terms of poly(A) tail length compared to polyadenylated hTR retrieved in the hTERT- and Dyskerin-bound fractions (P-value=5.551e-16, Kolmogorov-Smirnov test), showing a tendency toward longer poly(A) tails in the PABPN1-bound fraction. The enrichment of telomerase RNA with long poly(A) tails in the PABPN1-bound fraction is consistent with a role of PABPN1 in a maturation pathway that depends on hTR 3’ end polyadenylation. Moreover, our results indicate that a fraction of hTERT and Dyskerin are associated with polyadenylated versions of hTR.
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Project description:Eukaryotic mRNAs undergo a cycle of transcription, nuclear export, and degradation. A major challenge is to obtain a global, quantitative view of these processes. Here we measured the genome-wide nucleocytoplasmic dynamics of mRNA in Drosophila cells by metabolic labeling in combination with cellular fractionation. By mathematical modeling of these data we determined rates of transcription, export and cytoplasmic decay for >5,000 genes. We characterized these kinetic rates and investigated links with mRNA features, RNA-binding proteins (RBPs) and chromatin states. We found prominent correlations between mRNA decay rate and transcript size, while nuclear export rates are linked to the size of the 3'UTR. Transcription, export and decay rates are each associated with distinct spectra of RBPs. Specific classes of genes, such as those encoding cytoplasmic ribosomal proteins, exhibit characteristic combinations of rate constants, suggesting modular control. Overall, transcription and decay rates have a major impact on transcript abundance, while nuclear export is of minor importance. Finally, correlations between rate constants suggest global coordination between the three processes. Our approach should be generally applicable to other cell systems and provides insights into the genome-wide nucleocytoplasmic kinetics of mRNA.
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