RNA sequestration regulates cell fate (Human)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE245940 | GEO | 2025/09/30
REPOSITORIES: GEO
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Project description:Recent studies have highlighted the significance of RNA condensates in governing various aspects of cellular RNA processing. Nonetheless, the functional roles and composition of RNA condensates in the context of cell fate specification have remained elusive. In this study, we conducted a comprehensive characterization of the coding and non-coding transcriptome within cytoplasmic condensates known as P-bodies across diverse developmental contexts and vertebrate species. Notably, our investigation unveiled that the dissolution of RNA condensates reprograms both human and mouse pluripotent stem cells into a blastomere-like state. Mechanistically, we observed a high enrichment of untranslated fate-instructive RNAs within P-bodies, subject to cell type-specific sequestration. Employing degron systems, we demonstrated that the acute loss of P-bodies facilitates the translation of stored mRNAs. Furthermore, our research identifies the AGO-miRNAs molecular node as central in orchestrating RNA sequestration in P-bodies in a context-dependent manner. Perturbing AGO proteins, RNA 3’ UTR length, or expression of selected miRNAs, profoundly reshapes the localization of RNAs within cells. Collectively, our findings illuminate how RNA processing within condensates drives essential aspects of lineage-specific cell fate trajectories across vertebrate species.
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Project description:Recent studies have highlighted the significance of RNA condensates in governing various aspects of cellular RNA processing. Nonetheless, the functional roles and composition of RNA condensates in the context of cell fate specification have remained elusive. In this study, we conducted a comprehensive characterization of the coding and non-coding transcriptome within cytoplasmic condensates known as P-bodies across diverse developmental contexts and vertebrate species. Notably, our investigation unveiled that the dissolution of RNA condensates reprograms both human and mouse pluripotent stem cells into a blastomere-like state. Mechanistically, we observed a high enrichment of untranslated fate-instructive RNAs within P-bodies, subject to cell type-specific sequestration. Employing degron systems, we demonstrated that the acute loss of P-bodies facilitates the translation of stored mRNAs. Furthermore, our research identifies the AGO-miRNAs molecular node as central in orchestrating RNA sequestration in P-bodies in a context-dependent manner. Perturbing AGO proteins, RNA 3’ UTR length, or expression of selected miRNAs, profoundly reshapes the localization of RNAs within cells. Collectively, our findings illuminate how RNA processing within condensates drives essential aspects of lineage-specific cell fate trajectories across vertebrate species.
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Project description:Recent studies have highlighted the significance of RNA condensates in governing various aspects of cellular RNA processing. Nonetheless, the functional roles and composition of RNA condensates in the context of cell fate specification have remained elusive. In this study, we conducted a comprehensive characterization of the coding and non-coding transcriptome within cytoplasmic condensates known as P-bodies across diverse developmental contexts and vertebrate species. Notably, our investigation unveiled that the dissolution of RNA condensates reprograms both human and mouse pluripotent stem cells into a blastomere-like state. Mechanistically, we observed a high enrichment of untranslated fate-instructive RNAs within P-bodies, subject to cell type-specific sequestration. Employing degron systems, we demonstrated that the acute loss of P-bodies facilitates the translation of stored mRNAs. Furthermore, our research identifies the AGO-miRNAs molecular node as central in orchestrating RNA sequestration in P-bodies in a context-dependent manner. Perturbing AGO proteins, RNA 3’ UTR length, or expression of selected miRNAs, profoundly reshapes the localization of RNAs within cells. Collectively, our findings illuminate how RNA processing within condensates drives essential aspects of lineage-specific cell fate trajectories across vertebrate species.
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Project description:Post-transcriptional regulation is increasingly recognized as pivotal in guiding the gene expression programs that instruct cell fate decisions. Recent studies have highlighted the significance of RNA condensates in modulating gene expression through RNA processing and translational control. Yet, the functional roles and composition of RNA condensates in the context of cell fate specification remain unclear. In this study, we leveraged Fluorescence-Activated Particle Sorting to profile the coding and non-coding transcriptome within cytoplasmic condensates known as P-bodies across diverse developmental contexts and vertebrate species. Our analyses revealed the highly conserved, cell type-specific sequestration of fate-instructive RNAs, which are translationally suppressed and stored within P-bodies. Using degron systems in both human and mouse pluripotent cells, we demonstrate that the acute dissolution of P-bodies facilitates the translation of mRNAs otherwise suppressed in condensates, including genes associated with zygotic genome activation and totipotency. Consistently, loss of RNA sequestration awakens the totipotency transcriptional program in human and mouse pluripotent cells. Mechanistically, we provide evidence that miRNAs play a pivotal role in orchestrating the sequestration of specific RNAs into P-bodies in a context-dependent manner. Accordingly, perturbing AGO2, alternative polyadenylation, and miRNA function profoundly reshapes the sequestration of RNAs into P-bodies and alters cell fate. We further identify mir-300/381 as a key repressor of the totipotent transcriptional state. Collectively, our findings connect RNA processing within condensates to cell fate decisions across vertebrate species.
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Project description:Post-transcriptional regulation is increasingly recognized as pivotal in guiding the gene expression programs that instruct cell fate decisions. Recent studies have highlighted the significance of RNA condensates in modulating gene expression through RNA processing and translational control. Yet, the functional roles and composition of RNA condensates in the context of cell fate specification remain unclear. In this study, we leveraged Fluorescence-Activated Particle Sorting to profile the coding and non-coding transcriptome within cytoplasmic condensates known as P-bodies across diverse developmental contexts and vertebrate species. Our analyses revealed the highly conserved, cell type-specific sequestration of fate-instructive RNAs, which are translationally suppressed and stored within P-bodies. Using degron systems in both human and mouse pluripotent cells, we demonstrate that the acute dissolution of P-bodies facilitates the translation of mRNAs otherwise suppressed in condensates, including genes associated with zygotic genome activation and totipotency. Consistently, loss of RNA sequestration awakens the totipotency transcriptional program in human and mouse pluripotent cells. Mechanistically, we provide evidence that miRNAs play a pivotal role in orchestrating the sequestration of specific RNAs into P-bodies in a context-dependent manner. Accordingly, perturbing AGO2, alternative polyadenylation, and miRNA function profoundly reshapes the sequestration of RNAs into P-bodies and alters cell fate. We further identify mir-300/381 as a key repressor of the totipotent transcriptional state. Collectively, our findings connect RNA processing within condensates to cell fate decisions across vertebrate species.
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Project description:Post-transcriptional regulation is pivotal in guiding the gene expression programs that instruct cell fate decisions. Recent studies emphasize the significance of biomolecular condensates in modulating gene expression through RNA processing and translational control. However, the functional roles of RNA condensates in the context of cell fate specification are unknown. In this study, we profiled the coding and non-coding transcriptome within intact biomolecular condensates known as P-bodies in diverse developmental contexts and vertebrate species. Our analyses revealed the conserved, cell type-specific sequestration of RNAs encoding key cell fate specifiers. Notably, P-body contents did not directly reflect gene expression profiles for a given cell type, but rather were enriched for transcripts characteristic of the preceding developmental stage, which are translationally suppressed and stored within P-bodies. We demonstrate that the forced degradation of P-bodies stimulates the translation of transcripts encoding fate-instructive factors, ultimately re-activating a totipotency transcriptional program in human and mouse pluripotent cells. Mechanistically, microRNAs (miRNAs) facilitate the sequestration of specific RNAs into P-bodies in a context-dependent manner. Accordingly, perturbing AGO2, alternative polyadenylation, and miRNA function profoundly reshapes the RNA content of P-bodies and alters cell fate. Furthermore, we show that adding a miRNA target sequence is sufficient to redirect transcripts to P-bodies and influence stem cell self-renewal. Collectively, our findings establish a direct link between biomolecular condensates and cell fate decisions across vertebrate species.
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Project description:Recent studies have emphasized the significance of biomolecular condensates in modulating gene expression through RNA processing and translational control. However, the functional roles of RNA condensates in cell fate specification remains poorly understood. Here, we profiled the coding and non-coding transcriptome within intact biomolecular condensates, specifically P-bodies, in diverse developmental contexts, spanning multiple vertebrate species. Our analyses revealed the conserved, cell type-specific sequestration of untranslated RNAs encoding key cell fate regulators. Notably, P-body contents did not directly reflect active gene expression profiles for a given cell type, but rather were enriched for translationally repressed transcripts characteristic of the preceding developmental stage. Mechanistically, microRNAs (miRNAs) direct the selective sequestration of RNAs into P-bodies in a context-dependent manner, and perturbing AGO2 or alternative polyadenylation profoundly reshapes P-body RNA content. Building on these mechanistic insights, we demonstrate that modulating P-body assembly or miRNA activity dramatically enhances both activation of a totipotency transcriptional program in naïve pluripotent stem cells as well as the programming of primed human embryonic cells towards the germ cell lineage. Collectively, our findings establish a direct link between biomolecular condensates and cell fate decisions across vertebrate species and provide a novel framework for harnessing condensate biology to expand clinically relevant cell populations.
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