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

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

PROVIDER: PRJNA633144 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11798514_1.fastq.gz	Fastqsanger.gz
	SRR11798514_2.fastq.gz	Fastqsanger.gz
	SRR11798515_1.fastq.gz	Fastqsanger.gz
	SRR11798515_2.fastq.gz	Fastqsanger.gz
	SRR11798516_1.fastq.gz	Fastqsanger.gz

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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.

2022-04-20 | GSE150680 | GEO

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]

2022-04-20 | GSE150673 | GEO

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 [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 stem cell pluripotency

Project description:Translational control has emerged as a fundamental regulatory layer of proteome complexity that governs cellular identity and functions. As initiation is the rate-limiting step of translation, we carried out an RNAi screen for key translation initiation factors required to maintain embryonic stem cell (ESC) identity. We identified eIF4A2 and defined its mechanistic action through Rps26-independent and -dependent ribosomes in translation initiation activation of mRNAs encoding pluripotency factors and the histone variant H3.3 with demonstrated roles in maintaining stem cell pluripotency. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent 2-cell transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Accordingly, knockdown of eIF4A2 disrupts ESC proteome causing the loss of ESC identity. Collectively, we establish a translational paradigm of the protein synthesis of pluripotency transcription factors and epigenetic regulators imposed on their established roles in controlling pluripotency.

2024-12-20 | GSE192843 | GEO

Inosine Induces Stemness Features in HA-CAR-T cells and Enhances Potency [ATAC-seq]

Project description:Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ HA-CAR-T cells commonly express CD39 and CD73, which mediate proximal steps in Ado generation. Here we sought to enhance HA-CAR-T cell potency by knocking out CD39, CD73 or adenosine receptor 2a (A2aR), but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced HA-CAR-T functionality. Similarly, and to a greater extent, exposure of HA-CAR-T cells to INO augmented HA-CAR-T cell function and induced hallmark features of T cell stemness. INO induced profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency HA-CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.

2023-12-18 | GSE250439 | GEO

Inosine Induces Stemness Features in HA-CAR-T cells and Enhances Potency [RNA-seq]

2023-12-18 | GSE250442 | GEO

eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of stem cell pluripotency.

Project description:Translational control has emerged as a fundamental regulatory layer of proteome complexity that governs cellular identity and functions. As initiation is the rate-limiting step of translation, we carried out an RNA interference screen for key translation initiation factors required to maintain embryonic stem cell (ESC) identity. We identified eukaryotic translation initiation factor 4A2 (eIF4A2) and defined its mechanistic action through ribosomal protein S26-independent and -dependent ribosomes in translation initiation activation of messenger RNAs (mRNAs) encoding pluripotency factors and the histone variant H3.3 with demonstrated roles in maintaining stem cell pluripotency. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent two-cell transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Accordingly, knockdown of eIF4A2 disrupts ESC proteome, causing the loss of ESC identity. Collectively, we establish a translational paradigm of the protein synthesis of pluripotency transcription factors and epigenetic regulators imposed on their established roles in controlling pluripotency.

| S-EPMC8967233 | biostudies-literature

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

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