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RIP-Seq of Eif4a2 in mouse embryonic stem cell

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE153456 | GEO | 2022/02/02

REPOSITORIES: GEO

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Interactome of Eif4a2 in mouse embryonic stem cells

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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 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.

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RIP-Seq of Eif4a2 in mouse embryonic stem cell

Project description:RIP-Seq of Eif4a2 in mouse embryonic stem cell

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

Project description: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. Here we show 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 properties to chemically inhibited eIF4A1. We demonstrate that eIF4A2 exerts it repressive effect by binding purine-rich motifs which are enriched in the 5’UTR directly upstream of the AUG start codon. The data supports a model whereby purine motifs towards the 3’ end of the 5’UTR are associated with increased ribosome occupancy and possible uORF activation similar to that observed for mRNAs affected by inhibited eIF4A1.

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Identify Flag-bound transcripts via RIP-seq

Project description:Identify Flag-bound transcripts via RIP-seq

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Selective translation mechanism through two paralogs of eukaryotic initiation factor 4A

Project description:Eukaryotic initiation factor (eIF) 4A is a DEAD-box RNA-binding protein that plays a pivotal role in translation initiation. Although mammals have two eIF4A paralogs, eIF4A1 and eIF4A2, their redundancy has been long assumed because of high homology and their functional difference has been poorly understood. Here we show that eIF4A paralogs employ differential translation programs. Ribosome profiling of eIF4A1- and eIF4A2-knockout HEK293T cell lines revealed that translation efficiency changes were divergent across transcriptome and distinct group of mRNAs were regulated by each paralog. Our analysis indicates that eIF4A1 and eIF4A2 facilitate translation of specific mRNAs.

2019-10-26 | GSE126298 | GEO

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