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M6A mRNA Methylation Facilitates Resolution of Naïve Pluripotency Towards Differentiation (Ribo-seq)

ABSTRACT: Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here we identify Mettl3, an N6-Methyladenosine (m6A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout pre-implantation epiblasts and naïve embryonic stem cells (ESCs) are depleted for m6A in mRNAs and yet, are viable. However, they fail to adequately terminate their naïve state, and subsequently undergo aberrant and restricted lineage priming at the post-implantation stage, leading to early embryonic lethality. m6A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo, and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE61996 | GEO | 2014/11/02

SECONDARY ACCESSION(S): PRJNA262909

REPOSITORIES: GEO

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m6A RNA Methylation is Critical for Adequate Exit from Naïve Pluripotency and Execution of Mammalian Development (Ribo-seq)

Project description:In this study we identify Mettl3, an m6A RNA modification writer, as a critical regulator for terminating naïve pluripotency and a positive maintainer of primed pluripotency in vitro and in vivo. Remarkably, Mettl3 knockout pre-implantation epiblasts and naïve ES cells, entirely lack m6A on coding mRNAs and are viable. Yet, they fail to adequately terminate the naïve pluripotent state, and subsequently undergo aberrant priming and early lineage commitment at the post-implantation stage. A comprehensive functional and genomic analysis involving profiling of m6A, RNA transcription and translation in Mettl3 wild-type and knockout pluripotent and differentiated cells, identified m6A as a critical determinant that destabilizes secondary naïve specific pluripotency genes Esrrb, Klf4 and Nanog, and restrains their transcript stability and translation efficiency. In summary, our findings provide for the first time evidence for a critical role for an mRNA epigenetic modification in early mammalian development in vivo, and identify a mechanism that functionally regulates mouse naïve and primed pluripotency in an opposing manner. Ribosome footprint (Ribo-Seq) was measured from mouse embryonic stem cells and mouse embriod bodies, in WT and Mettl3-KO cell lines.

2014-11-02 | E-GEOD-61996 | biostudies-arrayexpress

m6A RNA Methylation is Critical for Adequate Exit from Naïve Pluripotency and Execution of Mammalian Development (RNA-Seq)

Project description:In this study we identify Mettl3, an m6A RNA modification writer, as a critical regulator for terminating naïve pluripotency and a positive maintainer of primed pluripotency in vitro and in vivo. Remarkably, Mettl3 knockout pre-implantation epiblasts and naïve ES cells, entirely lack m6A on coding mRNAs and are viable. Yet, they fail to adequately terminate the naïve pluripotent state, and subsequently undergo aberrant priming and early lineage commitment at the post-implantation stage. A comprehensive functional and genomic analysis involving profiling of m6A, RNA transcription and translation in Mettl3 wild-type and knockout pluripotent and differentiated cells, identified m6A as a critical determinant that destabilizes secondary naïve specific pluripotency genes Esrrb, Klf4 and Nanog, and restrains their transcript stability and translation efficiency. In summary, our findings provide for the first time evidence for a critical role for an mRNA epigenetic modification in early mammalian development in vivo, and identify a mechanism that functionally regulates mouse naïve and primed pluripotency in an opposing manner. polyA RNA-seq was measured in mouse embryonic stem cells (ESCs) and embroid bodies (EBs), each in WT and in Mettl3-KO cell lines. RNA-seq was measured also from WT mouse embronic fibroblasts (MEF). 3 biological replicates are available from ESCs and 2 from EBs. Replicate C in ESCs was measured alongside protein levels (SILAC) and was used for the analysis of that assay.

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Project description:Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N6-methyladenosine (m6A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout pre-implantation epiblasts and naïve embryonic stem cells (ESCs) are depleted for m6A in mRNAs and yet, are viable. However, they fail to adequately terminate their naïve state, and subsequently undergo aberrant and restricted lineage priming at the post-implantation stage, leading to early embryonic lethality. m6A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo, and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner.

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m6A mRNA Methylation Facilitates Resolution of Naïve Pluripotency Towards Differentiation (m6a-seq)

Project description:Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here we identify Mettl3, an N6-Methyladenosine (m6A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout pre-implantation epiblasts and naïve embryonic stem cells (ESCs) are depleted for m6A in mRNAs and yet, are viable. However, they fail to adequately terminate their naïve state, and subsequently undergo aberrant and restricted lineage priming at the post-implantation stage, leading to early embryonic lethality. m6A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo, and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner.

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2014-11-02 | GSE61994 | GEO

m6A RNA Methylation is Critical for Adequate Exit from NaM-CM-/ve Pluripotency and Execution of Mammalian Development (3p-Seq)

Project description:In this study we identify Mettl3, an m6A RNA modification writer, as a critical regulator for terminating naM-CM-/ve pluripotency and a positive maintainer of primed pluripotency in vitro and in vivo. Remarkably, Mettl3 knockout pre-implantation epiblasts and naM-CM-/ve ES cells, entirely lack m6A on coding mRNAs and are viable. Yet, they fail to adequately terminate the naM-CM-/ve pluripotent state, and subsequently undergo aberrant priming and early lineage commitment at the post-implantation stage. A comprehensive functional and genomic analysis involving profiling of m6A, RNA transcription and translation in Mettl3 wild-type and knockout pluripotent and differentiated cells, identified m6A as a critical determinant that destabilizes secondary naM-CM-/ve specific pluripotency genes Esrrb, Klf4 and Nanog, and restrains their transcript stability and translation efficiency. In summary, our findings provide for the first time evidence for a critical role for an mRNA epigenetic modification in early mammalian development in vivo, and identify a mechanism that functionally regulates mouse naM-CM-/ve and primed pluripotency in an opposing manner. 3' polyA RNA-sequencing (equivalent to Digital Gene Expression) measured in mouse Embryonic Stem Cells (ESCs) and mouse Embriod bodies (EBs) 0,4 & 8 hours after treatment with Actinomycin which halts transcription. Measured in both WT and Mettl3-KO cells.

2014-11-02 | E-GEOD-61994 | biostudies-arrayexpress

m6A RNA Methylation is Critical for Adequate Exit from NaM-CM-/ve Pluripotency and Execution of Mammalian Development (m6a-seq)

Project description:In this study we identify Mettl3, an m6A RNA modification writer, as a critical regulator for terminating naM-CM-/ve pluripotency and a positive maintainer of primed pluripotency in vitro and in vivo. Remarkably, Mettl3 knockout pre-implantation epiblasts and naM-CM-/ve ES cells, entirely lack m6A on coding mRNAs and are viable. Yet, they fail to adequately terminate the naM-CM-/ve pluripotent state, and subsequently undergo aberrant priming and early lineage commitment at the post-implantation stage. A comprehensive functional and genomic analysis involving profiling of m6A, RNA transcription and translation in Mettl3 wild-type and knockout pluripotent and differentiated cells, identified m6A as a critical determinant that destabilizes secondary naM-CM-/ve specific pluripotency genes Esrrb, Klf4 and Nanog, and restrains their transcript stability and translation efficiency. In summary, our findings provide for the first time evidence for a critical role for an mRNA epigenetic modification in early mammalian development in vivo, and identify a mechanism that functionally regulates mouse naM-CM-/ve and primed pluripotency in an opposing manner. m6A-seq was measured from total RNA in mouse embryonic stem cells (ESCs), embroid bodies (EBs) and embronic fibroblasts (MEF). 3 biological replicates are available from BVSC ESC line and EBs, and two biological replicates are available for MEFs. Each sample consist of IP to m6A and control input

2014-11-02 | E-GEOD-61995 | biostudies-arrayexpress

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Project description:Naïve human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naïve hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naïve hESCs, indicating that PRODH maintains naïve pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naïve pluripotency of hESCs. Untargeted metabolomics - H9N PLKO.1 vs H9P PLKO.1 / H9P shPRODH vs H9P PLKO.1 / H9N shPRODH vs H9N PLKO.1 - is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS7840' rel='noopener noreferrer' target='_blank'>MTBLS7840</a>.Targeted metabolomics (amino acids and derivatives) - H9P (Primed) VS H9N (Naïve) - is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7832' rel='noopener noreferrer' target='_blank'>MTBLS7832</a>.

2024-02-12 | MTBLS7840 | MetaboLights

PRODH regultes naive pluripotency by influencing mitochondrial oxidative phosphorylation (Targeted metabolomics)

Project description:Naïve human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naïve hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naïve hESCs, indicating that PRODH maintains naïve pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naïve pluripotency of hESCs. Targeted metabolomics (amino acids and derivatives) - H9P (Primed) VS H9N (Naïve) - is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS7832' rel='noopener noreferrer' target='_blank'>MTBLS7832</a>.Untargeted metabolomics - H9N PLKO.1 vs H9P PLKO.1 / H9P shPRODH vs H9P PLKO.1 / H9N shPRODH vs H9N PLKO.1 - is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7840' rel='noopener noreferrer' target='_blank'>MTBLS7840</a>.

2024-02-12 | MTBLS7832 | MetaboLights

Sirtuin 1 Promotes Naïve Pluripotency by Deacetylation of Oct4 (RNA-seq)

Project description:The enhancer landscape is dramatically restructured as naïve preimplantation epiblasts transition to the post-implantation state of primed pluripotency. A key factor in this process is Otx2, which is upregulated during the early stages of this transition and ultimately recruits Oct4 to a different set of enhancers. In this study we discover that the acetylation status of Oct4 regulates the induction of the primed pluripotency gene network. Maintenance of the naïve state requires Oct4 deacetylation by the NAD-dependent deacetylase, SirT1. The activity of SirT1 is reduced during the naïve to primed transition, thereby increasing the acetylation of Oct4 and promoting its binding to an Otx2 enhancer to induce Otx2 expression. Induction of Otx2 causes the reorganization of acetylated Oct4 and results in the induction of the primed pluripotency gene network. Regulation of Oct4 by SirT1 may link stem cell development to environmental conditions and provide strategies to manipulate epiblast cell state.

2016-09-20 | GSE81494 | GEO

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