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Translational control of developmental potency and histone variant transcripts safeguards embryonic stem cell identity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE150682 | GEO | 2022/04/20

REPOSITORIES: GEO

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Translational control of developmental potency and histone variant transcripts safeguards embryonic stem cell identity

Project description:Translational control of developmental potency and histone variant transcripts safeguards embryonic stem cell identity

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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 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.

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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]

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The histone chaperone CAF-1 safeguards somatic cell identity.

Project description:Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Chaf1a and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting.

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ABHD4-dependent developmental anoikis safeguards the embryonic brain.

Project description:A specialized neurogenic niche along the ventricles accumulates millions of progenitor cells in the developing brain. After mitosis, fate-committed daughter cells delaminate from this germinative zone. Considering the high number of cell divisions and delaminations taking place during embryonic development, brain malformations caused by ectopic proliferation of misplaced progenitor cells are relatively rare. Here, we report that a process we term developmental anoikis distinguishes the pathological detachment of progenitor cells from the normal delamination of daughter neuroblasts in the developing mouse neocortex. We identify the endocannabinoid-metabolizing enzyme abhydrolase domain containing 4 (ABHD4) as an essential mediator for the elimination of pathologically detached cells. Consequently, rapid ABHD4 downregulation is necessary for delaminated daughter neuroblasts to escape from anoikis. Moreover, ABHD4 is required for fetal alcohol-induced apoptosis, but not for the well-established form of developmentally controlled programmed cell death. These results suggest that ABHD4-mediated developmental anoikis specifically protects the embryonic brain from the consequences of sporadic delamination errors and teratogenic insults.

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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 [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 [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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