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EIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [Ribo-seq]

ABSTRACT: Stemness is a defining feature in embryonic and cancer stem cells. How stemness is regulated at the mRNA translational initiation remains undefined. We carried out an RNAi screen for key translation initiation factors that maintain the stemness in mouse embryonic stem cells (ESCs). We identified eIF4A2 and defined its mechanistic action through Rps26-depleted and -containing ribosomes in translational initiation activation of mRNAs encoding pluripotency factors and H3.3 for embryonic and extraembryonic lineage repression, respectively. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent 2-cell (2C) transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Knockdown of eIF4A2 disrupts ESC proteome causing the loss of stemness in ESCs as well as in human glioblastomas where eIF4A2 is highly enriched. Collectively, our study establishes an eIF4A2-mediated translation initiation control of stemness and provides insight into cancer therapeutics targeting the translation initiation machinery.

ORGANISM(S): Mus musculus

PROVIDER: GSE150676 | GEO | 2022/04/20

REPOSITORIES: GEO

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eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [eCLIP-seq]

Project description:Stemness is a defining feature in embryonic and cancer stem cells. How stemness is regulated at the mRNA translational initiation remains undefined. We carried out an RNAi screen for key translation initiation factors that maintain the stemness in mouse embryonic stem cells (ESCs). We identified eIF4A2 and defined its mechanistic action through Rps26-depleted and -containing ribosomes in translational initiation activation of mRNAs encoding pluripotency factors and H3.3 for embryonic and extraembryonic lineage repression, respectively. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent 2-cell (2C) transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Knockdown of eIF4A2 disrupts ESC proteome causing the loss of stemness in ESCs as well as in human glioblastomas where eIF4A2 is highly enriched. Collectively, our study establishes an eIF4A2-mediated translation initiation control of stemness and provides insight into cancer therapeutics targeting the translation initiation machinery.

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eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [RNA-seq]

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RIP-Seq of Eif4a2 in mouse embryonic stem cell

Project description:RNA-immunoprecipitation can be used to identify transcripts bound by RNA binding proteins. Here we identified transcripts bound by the translation initiation factor Eif4a2 in ESCs. We found that several pluripotency transcription factor encoding mRNAs and factors regulating ESC differentiation show binding to Eif4a2 stronger than expected by transcript abundance.

2022-02-02 | GSE153456 | GEO

Interactome of Eif4a2 in mouse embryonic stem cells

Project description:Cell fate transitions depend on balanced rewiring of transcription and translation programmes to enable ordered developmental progression. We identified a feedback loop between nonsense-mediated mRNA decay (NMD) and translation initiation, in which NMD controls the translation initiation factor Eif4a2 and its premature termination codon encoding isoform (Eif4a2-PTC). This leads to translation of a specific truncated protein, which elicits increased translation rates and is causative for significant delays in mouse embryonic stem cell differentiation. Using immunoprecipitation coupled with mass spectrometry, we identified the interactome of full length Eif4a2 (Eif4a2-iso1) and Eif4a2-PTC. We find that Eif4a2-iso1 is mainly involved in translation initiation, while unstable Eif4a2-PTC shows little interaction with translation initiation factors. Both isoforms can bind to mRNA, as indicated by the interaction with mRNA binding protein, such as NMD factors and Ago2. Finally, Eif4a2-iso1 and Eif4a2-PTC interact with key pluripotency factors, providing a potential explanation for how Eif4a2 controls ESC differentiation.

2022-03-09 | PXD019588 | Pride

eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5’UTR

Project description:Background: Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Results: Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4- Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA-selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5’UTR of target mRNAs directly upstream of the AUG start codon. Conclusions: Our data support a model whereby purine motifs towards the 3’ end of the 5’UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding.

2019-10-09 | GSE94690 | GEO

eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine rich motifs in th 5'UTR

Project description:Here we show eIF4A2 is a major effector of the represive miRNA pathway functioning via the Ccr4_Not complex; through its interaction with the Ccr4-Not complex eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar properties to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5'UTR directly upstream of the AUG codon.

2019-10-10 | PXD015772 | Pride

eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [Ribo-seq]

Project description:eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [Ribo-seq]

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eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [RNA-seq]

Project description:eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [RNA-seq]

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eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [eCLIP-seq]

Project description:eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [eCLIP-seq]

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DDX6 decouples translational repression from RNA degradation of miRNA targets [Ribosome Profiling]

Project description:Translation and mRNA degradation are intimately connected, yet the mechanisms that regulate them are not fully understood. Here we examine the regulation of translation and mRNA stability in mouse embryonic stem cells (ESCs) and during differentiation. In contrast to previous reports, we found that transcriptional changes account for most of the molecular changes during ESC differentiation. Within ESCs translation level and mRNA stability are positively correlated. The RNA-binding protein DDX6 has been implicated in processes involving both translational repression and mRNA destabilization; in yeast DDX6 connects codon optimality and mRNA stability and in mammals DDX6 is involved in microRNA-mediated repression. We generated DDX6 KO ESCs and found that while there was minimal connection between codon usage and stability changes, the loss of DDX6 leads to the translational depression of microRNA targets. Surprisingly, the translational derepression of microRNA targets occurs without affecting mRNA stability. Furthermore, DDX6 KO ESCs share overlapping phenotypes and global molecular changes with ESCs that completely lack all microRNAs. Together our results demonstrate that the loss of DDX6 decouples the two forms of microRNA induced repression and emphasize that translational repression by microRNAs is underappreciated.

2018-07-25 | GSE112766 | GEO

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