A translational repression complex in developing mammalian neural stem cells that regulates neuronal specification
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ABSTRACT:
PROVIDER: PRJNA427160 | ENA |
REPOSITORIES: ENA
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Project description:The mechanisms instructing genesis of neuronal subtypes from mammalian neural precursors are not well-understood. To address this issue, we have characterized the transcriptional landscape of radial glial precursors (RPs) in the embryonic murine cortex. We show that individual RPs express mRNA but not protein for transcriptional specifiers of both deep and superficial layer cortical neurons. Some of these mRNAs, including the superficial versus deep layer neuron transcriptional regulators Brn1 and Tle4, are translationally repressed by their association with the RNA-binding protein Pumilio2 and the 4E-T protein. When these repressive complexes are disrupted in RPs mid-neurogenesis by knocking down 4E-T or Pum2, this causes aberrant co-expression of deep layer neuron specification proteins in newborn superficial neurons. Thus, cortical RPs are transcriptionally primed to generate diverse types of neurons, and a 4E-T-Pum2 complex represses translation of some of these neuronal identity mRNAs to ensure appropriate temporal specification of daughter neurons.
2018-01-26 | GSE108404 | GEO
Project description:CRISPRδ: dCas13-mediated translational repression for accurate gene silencing in mammalian cells
| PRJNA971898 | ENA
Project description:MicroRNAs (miRNAs) regulate target mRNAs through a combination of translational repression and mRNA destabilization, with mRNA destabilization dominating at steady state in the few contexts examined globally. Here, we extend the global steady-state measurements to many additional mammalian contexts and find that regardless of the miRNA, cell type, growth condition or translational state, mRNA destabilization explains most (70% to >90%) miRNA-mediated repression. We also determine the relative dynamics of translational repression and mRNA destabilization for endogenous mRNAs as a miRNA is induced. Although translational repression occurs rapidly, its effect on gene expression is relatively weak, such that by the time consequential repression ensues, the effect of mRNA destabilization dominates. These results add to the fundamental understanding of miRNAs, imply that consequential miRNA-mediated repression is largely irreversible and simplify future studies, dramatically extending the known contexts and time points for which monitoring mRNA changes captures most of the direct miRNA effects. 6 samples from a variety of primary cell types
2014-09-25 | E-GEOD-60976 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) regulate target mRNAs through a combination of translational repression and mRNA destabilization, with mRNA destabilization dominating at steady state in the few contexts examined globally. Here, we extend the global steady-state measurements to additional mammalian contexts and find that regardless of the miRNA, cell type, growth condition, or translational state, mRNA destabilization explains most (66%–>90%) miRNA-mediated repression. We also determine the relative dynamics of translational repression and mRNA destabilization for endogenous mRNAs as a miRNA is induced. Although translational repression occurs rapidly, its effect is relatively weak, such that by the time consequential repression ensues, the effect of mRNA destabilization dominates. These results imply that consequential miRNA-mediated repression is largely irreversible and provide other insights into the nature of miRNA-mediated regulation. They also simplify future studies, dramatically extending the known contexts and time points for which monitoring mRNA changes captures most of the direct miRNA effects.
2014-09-25 | GSE60426 | GEO
Project description:Malaria parasites must be able to respond quickly to their environment, including during their transmission between mammalian hosts and mosquito vectors. Therefore, before transmission, female gametocytes proactively produce and translationally repress mRNAs that encode essential proteins that the zygote requires to establish a new infection. This essential regulatory control requires the orthologues of DDX6 (DOZI) and LSM14 (CITH), which along with ALBA proteins, form a translationally repressive complex in female gametocytes that associates with many of the affected mRNAs. However, while the release of translational repression of individual mRNAs has been documented, the details of the global release of translational repression have not. Moreover, the changes in spatial arrangement and composition of the DOZI/CITH/ALBA complex that contribute to translational control are also not known. Therefore, we have conducted the first comparative transcriptomics and proteomics of Plasmodium parasites across the host-to-vector transmission event to document the global release of translational repression. Using female gametocytes and zygotes of P. yoelii, we find that over 200 transcripts are released for translation soon after fertilization, including those with essential functions for the zygote. However, we also observed that some transcripts remain repressed beyond this point. In addition, we have used TurboID-based proximity proteomics to interrogate the spatial and compositional changes in the DOZI/CITH/ALBA complex across this transmission event. Consistent with recent models of translational control, proteins that associate with either the 5’ or 3’ end of mRNAs are in close proximity to one another during translational repression in female gametocytes and then dissociate upon release of repression in zygotes. These protein interactions in female gametocytes were further validated through structured illumination microscopy and ultrastructure expansion microscopy. Together, these data provide a model for the essential translational control mechanisms used by malaria parasites to promote their efficient transmission.
2023-05-10 | GSE231838 | GEO
Project description:MicroRNAs (miRNAs) regulate target mRNAs through a combination of translational repression and mRNA destabilization, with mRNA destabilization dominating at steady state in the few contexts examined globally. Here, we extend the global steady-state measurements to many additional mammalian contexts and find that regardless of the miRNA, cell type, growth condition or translational state, mRNA destabilization explains most (70% to >90%) miRNA-mediated repression. We also determine the relative dynamics of translational repression and mRNA destabilization for endogenous mRNAs as a miRNA is induced. Although translational repression occurs rapidly, its effect on gene expression is relatively weak, such that by the time consequential repression ensues, the effect of mRNA destabilization dominates. These results add to the fundamental understanding of miRNAs, imply that consequential miRNA-mediated repression is largely irreversible and simplify future studies, dramatically extending the known contexts and time points for which monitoring mRNA changes captures most of the direct miRNA effects.
2014-09-25 | GSE60976 | GEO
Project description:Current gene silencing tools based on RNA interference (RNAi) or more recently the CRISPR-Cas13 systems have critical drawbacks in such as off-target effects (RNAi) or collateral mRNA cleavage (CRISPR-Cas13). Thus, a more specific method of gene knockdown has been demanded. Here we developed “CRISPRδ”, an approach for translational silencing, harnessing the catalytically inactive Cas13 proteins (dCas13). Owing to the tight association with mRNA, dCas13 serves as a physical roadblock for scanning ribosomes in translation initiation, but not for elongating ribosomes, with no effect on mRNA stability. Guide RNAs covering the start codon lead to the highest efficacy, irrespective of translation initiation mechanisms: cap-dependent, IRES-dependent, or RAN translations. Strikingly, genome-wide ribosome profiling revealed extremely high specificity of CRISPRδ in a gene knockdown. Moreover, the fusion of a translation repressor to dCas13 ensured further improvement of the knockdown efficacy. Our method provides a framework for translational repression-based gene silencing in eukaryotes.
2024-02-10 | GSE232383 | GEO
Project description:The degree and dynamics of translational control during mammalian development remain poorly understood. Here we monitored translation of the mammalian genome as cells become specified and organize into tissues in vivo. This identified unexpected and pervasive translational regulation of most of the core signalling circuitry including Shh,Wnt, Hippo, PI3K and MAPK pathways. We further identify and functionally characterize a complex landscape of upstream open reading frames (uORFs) across 5'-untranslated regions (UTRs) of key signalling components. Focusing on the Shh pathway, we demonstrate the importance of uORFs within the major SHH receptor, Ptch1, in control of cell signalling and neuronal differentiation. Finally, we show that the expression of hundreds of mRNAs underlying critical tissue-specific developmental processes is largely regulated at the translation but not transcript levels. Altogether, this work reveals a new layer of translational control to major signalling components and gene regulatory networks that diversifies gene expression spatially across developing tissues.
2017-01-20 | GSE86467 | GEO
Project description:eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition
| PRJNA763797 | ENA
Project description:Eukaryotic translation initiation factor (eIF) 4A — a DEAD-box RNA-binding protein — plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here, we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs (TOP mRNAs), whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the affinity between TOP mRNAs and LARP1 and thus ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator.
2024-02-13 | GSE184247 | GEO