NELFA is a novel regulator of the 2C-like state
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA453559 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10486972_1.fastq.gz | Fastqsanger.gz | |||
| SRR10486972_2.fastq.gz | Fastqsanger.gz | |||
| SRR10486973_1.fastq.gz | Fastqsanger.gz | |||
| SRR10486973_2.fastq.gz | Fastqsanger.gz | |||
| SRR10486974_1.fastq.gz | Fastqsanger.gz |
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Project description:Mouse embryonic stem cells (mESCs) are not homogenous; a rare subpopulation of cells can sporadically transit into a early-embryonic-like state and exhibits a gene expression program resembling that of the 2-cell (2C) embryo. We identified the maternal factor NELFA as a novel driver of the 2C-like gene expression through multiple mechanisms. We further demonstrate that the entry of mESCs into the 2C-like state is accompanied by epigenetic and metabolic reprogramming, and that perturbation of the metabolic state via a small molecule can promote this cell fate reversion in a NELFA-dependent manner, obviating the need for any genetic manipulation. Our findings thus place NELFA as one of the earliest regulators of 2C gene expression, extending contemporary knowledge of how totipotency may be regulated.
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Project description:Mouse embryonic stem cells (ESCs) consist of a rare population of heterogeneous cells which express 2-cell-stage-specific transcripts and are referred to as 2-cell-like cells (2CLCs). Accumulating evidence has demonstrated that transcription factors and epigenetic modifications exert crucial functions in the transition of ESCs to 2CLCs. However, the roles of RNA modification in the regulation of 2C-like state remain elusive. Using Dux-induced 2CLCs system, we examine N6-methyladenosine (m6A) modification landscape in transcriptome-wide, and find that m6A is dynamically regulated during Dux-driven 2C-like reprogramming. Intriguingly, many of 2C-specific transcripts are highly methylated, including Dux and Zscan4 cluster genes. We further identify the m6A reader protein Ythdf2 as a critical regulator of 2C-like state. Depletion of Ythdf2 facilitates robust expressions of 2C transcripts and the transition of ESCs to 2CLCs. Mechanically, Ythdf2 binds to the Dux/Zscan4 transcripts and promotes their degradation through recruiting the key component of RNA deadenylase complex, Cnot1. Consistent with the phenotype of Ythdf2 deficiency, silencing of Cnot1 induces the 2C gene expressions and the transition of ESCs into the 2C-like state. Collectively, our findings reveal novel insights into the epitranscriptomic regulation of the 2C-like state in mouse ESCs.
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Project description:Mouse embryonic stem cells (ESCs) consist of a rare population of heterogeneous cells which express 2-cell-stage-specific transcripts and are referred to as 2-cell-like cells (2CLCs). Accumulating evidence has demonstrated that transcription factors and epigenetic modifications exert crucial functions in the transition of ESCs to 2CLCs. However, the roles of RNA modification in the regulation of 2C-like state remain elusive. Using Dux-induced 2CLCs system, we examine N6-methyladenosine (m6A) modification landscape in transcriptome-wide, and find that m6A is dynamically regulated during Dux-driven 2C-like reprogramming. Intriguingly, many of 2C-specific transcripts are highly methylated, including Dux and Zscan4 cluster genes. We further identify the m6A reader protein Ythdf2 as a critical regulator of 2C-like state. Depletion of Ythdf2 facilitates robust expressions of 2C transcripts and the transition of ESCs to 2CLCs. Mechanically, Ythdf2 binds to the Dux/Zscan4 transcripts and promotes their degradation through recruiting the key component of RNA deadenylase complex, Cnot1. Consistent with the phenotype of Ythdf2 deficiency, silencing of Cnot1 induces the 2C gene expressions and the transition of ESCs into the 2C-like state. Collectively, our findings reveal novel insights into the epitranscriptomic regulation of the 2C-like state in mouse ESCs.
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Project description:In mouse embryonic stem cell (ESC) culture, a small proportion of cells display totipotent features by expressing a set of genes that are only active in 2-cell-stage embryos. These 2-cell-like (2C-like) cells spontaneously transit back into pluripotent state. We previously dissected the transcriptional dynamics of pluripotent to 2C-like transition and identified factors that modulate the transition. However, how 2C-like cells transits back to the pluripotent state and what factors drive this process remains largely unknown. To address these questions, we examined the transcriptional dynamics during the reverse transition from the 2C-like state to ESCs and identified an intermediate state involved in the transition. Interestingly, we found that mESCs exit from the 2C-like state through a molecular path characterized by a two-wave upregulation of pluripotent genes different from the one observed during the 2C-like entry transition. We also showed that nonsense-mediated mRNA decay (NMD) targets Dux mRNA and affects 2C-like state maintenance, suggesting that Dux degradation contributes to the reversal of 2C-like state.
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Project description:In mouse embryonic stem cell (ESC) culture, a small proportion of cells display totipotent features by expressing a set of genes that are only active in 2-cell-stage embryos. These 2-cell-like (2C-like) cells spontaneously transit back into pluripotent state. We previously dissected the transcriptional dynamics of pluripotent to 2C-like transition and identified factors that modulate the transition. However, how 2C-like cells transits back to the pluripotent state and what factors drive this process remains largely unknown. To address these questions, we examined the transcriptional dynamics during the reverse transition from the 2C-like state to ESCs and identified an intermediate state involved in the transition. Interestingly, we found that mESCs exit from the 2C-like state through a molecular path characterized by a two-wave upregulation of pluripotent genes different from the one observed during the 2C-like entry transition. We also showed that nonsense-mediated mRNA decay (NMD) targets Dux mRNA and affects 2C-like state maintenance, suggesting that Dux degradation contributes to the reversal of 2C-like state.
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