The metabolome regulates the epigenetic landscape during naïve to primed human embryonic stem cell transition
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ABSTRACT:
PROVIDER: PRJNA259889 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1561941_1.fastq.gz | Fastqsanger.gz | |||
| SRR1561941_2.fastq.gz | Fastqsanger.gz | |||
| SRR1561942_1.fastq.gz | Fastqsanger.gz | |||
| SRR1561942_2.fastq.gz | Fastqsanger.gz | |||
| SRR1561943_1.fastq.gz | Fastqsanger.gz |
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Project description:For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans exhibit two stable yet epigenetically distinct states of pluripotency: naive and primed. We now show that nicotinamide N-methyltransferase (NNMT) and the metabolic state regulate pluripotency in human embryonic stem cells (hESCs). Specifically, in naive hESCs, NNMT and its enzymatic product 1-methylnicotinamide are highly upregulated, and NNMT is required for low S-adenosyl methionine (SAM) levels and the H3K27me3 repressive state. NNMT consumes SAM in naive cells, making it unavailable for histone methylation that represses Wnt and activates the HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development.
| S-EPMC4662931 | biostudies-literature
Project description:We performed mRNA-seq and small RNA-seq on the newly derived ELF human naïve pluripotent stem cell line and compared with the existing H1 human primed line. Expression analysis revealed that mitochondria oxidative phosphorylation and fatty acid beta-oxidaton is up-regulated in naive state while fatty acid synthesis is up-regulated in primed state. Small RNA-seq revealed consistent expression changes in microRNAs that target key fatty acid beta-oxidation and synthesis genes. Integration with metabolomics data revealed consistent changes in the expression of NNMT (higher in naive state) and IDO1 (higher in primed state) and in the concentration of corresponding metabolic substrates and products. As a regulator of S-Adenosyl methionine (SAM) level, NNMT is proposed as a candidate regulator of epigenetic states. ChIP-seq analysis releaved that naive lines have lower H3K27me3 marks in developmental genes. Inhibition of STAT3, a known regulator of NNMT, reduces NNMT expression level and decreases overall H3K27me3 marks around transcriptional start sites. In particular, STAT3 inhibitor treatment increased H3K27me3 marks in 313 genes that also have higher H3K27me3 marks in primed state than naive state. These 313 genes are enriched with developmental functions, and include several WNT pathway genes. In summary, integrative analysis of RNA-seq, ChIP-seq and metabolomics data revealed key metabolic differences between naive and primed pluripotency and identified NNMT as a key regulator of epigeneitc state.
2015-11-17 | GSE60955 | GEO
Project description:Translational control plays a central role in regulation of gene expression and can lead to significant divergence between mRNA- and protein-abundance. The translational landscape of early mammalian development and its impact on cellular proteome, however, remains largely un-explored. Here we used genome-wide approaches combined with time-course analysis to measure the mRNA-abundance, mRNA-translation rate and protein expression during the transition of naïve into primed embryonic stem cells (ESCs). We found that the ground state ESCs cultured with GSK3- and MEK-inhibitors and LIF (2iL) display higher ribosome density on a selective set of mRNAs. These mRNAs show reduced translation during the exit from ground state pluripotency and transition to serum/LIF (SL) culture or upon commitment to primed epiblast-like stem cells (EpiLSCs). Strikingly, integrative analysis with cellular proteome indicate a strong translational buffering of this set of mRNAs in 2iL-ESCs leading to stable protein expression levels. Our data reveal that the global alteration of cellular proteome is largely accompanied by transcriptional rewiring. Furthermore, we identified a set of genes (including UHRF1 and KRAS) that undergo selective post-translational regulation during the transition of naïve into primed pluripotency and linked the observed changes to upstream GSK- and MEK/MAPK-signaling pathways using single inhibitor treated ESCs. Thus, we provide a comprehensive and detailed overview of the global changes in gene expression during the transition of naïve to primed pluripotency and dissect the relative contributions of RNA-transcription, translation and regulation of protein stability in controlling protein abundance.
2020-04-03 | PXD014528 | Pride
Project description:Autophagy is a conserved cellular mechanism to degrade unwanted cytoplasmic proteins and organelles to recycle their components, and it is proved to be critical for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. However, the role of autophagy in embryonic development remains elusive, and no information exists regarding its functions during the transition from naive to primed pluripotency. Here by using an in vitro transition model of ESCs to epiblast-like cells (EpiLCs), we describe that the dynamic changes in Atg7-dependent autophagy is required for the naive to primed transition, and it is also necessary for germline specification. RNA-seq and ATAC-seq profiling reveal that Nanog acts as a barrier to prevent pluripotency transition, and autophagy-dependent Nanog degradation is important for dismantling the naive pluripotency expression program through decommissioning of naive-associated active enhancers. Mechanistically, we found that autophagy adaptor protein Sqstm1 (p62) is nucleus located during the pluripotency transition period and it is preferentially associated with ubiquitinated Nanog for selective protein degradation. In vivo, loss of autophagy by Atg7 depletion disrupts peri-implantation development and we observed increased chromatin association of Nanog, which affects neuronal differentiation through activation of a subset of neuroectodermal development-associated enhancers. Taken together, our findings illuminate regulatory mechanisms underlying the naive to primed transition and reveal that autophagy-dependent regulation of Nanog is essential for exit from the naive state and marks distinct cell fate allocation during lineage specification.
2020-11-07 | GSE160976 | GEO
Project description:Autophagy is a conserved cellular mechanism to degrade unwanted cytoplasmic proteins and organelles to recycle their components, and it is proved to be critical for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. However, the role of autophagy in embryonic development remains elusive, and no information exists regarding its functions during the transition from naive to primed pluripotency. Here by using an in vitro transition model of ESCs to epiblast-like cells (EpiLCs), we describe that the dynamic changes in Atg7-dependent autophagy is required for the naive to primed transition, and it is also necessary for germline specification. RNA-seq and ATAC-seq profiling reveal that Nanog acts as a barrier to prevent pluripotency transition, and autophagy-dependent Nanog degradation is important for dismantling the naive pluripotency expression program through decommissioning of naive-associated active enhancers. Mechanistically, we found that autophagy adaptor protein Sqstm1 (p62) is nucleus located during the pluripotency transition period and it is preferentially associated with ubiquitinated Nanog for selective protein degradation. In vivo, loss of autophagy by Atg7 depletion disrupts peri-implantation development and we observed increased chromatin association of Nanog, which affects neuronal differentiation through activation of a subset of neuroectodermal development-associated enhancers. Taken together, our findings illuminate regulatory mechanisms underlying the naive to primed transition and reveal that autophagy-dependent regulation of Nanog is essential for exit from the naive state and marks distinct cell fate allocation during lineage specification.
2020-07-22 | GSE154860 | GEO
Project description:Autophagy is a conserved cellular mechanism to degrade unwanted cytoplasmic proteins and organelles to recycle their components, and it is proved to be critical for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. However, the role of autophagy in embryonic development remains elusive, and no information exists regarding its functions during the transition from naive to primed pluripotency. Here by using an in vitro transition model of ESCs to epiblast-like cells (EpiLCs), we describe that the dynamic changes in Atg7-dependent autophagy is required for the naive to primed transition, and it is also necessary for germline specification. RNA-seq and ATAC-seq profiling reveal that Nanog acts as a barrier to prevent pluripotency transition, and autophagy-dependent Nanog degradation is important for dismantling the naive pluripotency expression program through decommissioning of naive-associated active enhancers. Mechanistically, we found that autophagy adaptor protein Sqstm1 (p62) is nucleus located during the pluripotency transition period and it is preferentially associated with ubiquitinated Nanog for selective protein degradation. In vivo, loss of autophagy by Atg7 depletion disrupts peri-implantation development and we observed increased chromatin association of Nanog, which affects neuronal differentiation through activation of a subset of neuroectodermal development-associated enhancers. Taken together, our findings illuminate regulatory mechanisms underlying the naive to primed transition and reveal that autophagy-dependent regulation of Nanog is essential for exit from the naive state and marks distinct cell fate allocation during lineage specification.
2020-05-20 | GSE150865 | GEO
Project description:Autophagy is a conserved cellular mechanism to degrade unwanted cytoplasmic proteins and organelles to recycle their components, and it is proved to be critical for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. However, the role of autophagy in embryonic development remains elusive, and no information exists regarding its functions during the transition from naive to primed pluripotency. Here by using an in vitro transition model of ESCs to epiblast-like cells (EpiLCs), we describe that the dynamic changes in Atg7-dependent autophagy is required for the naive to primed transition, and it is also necessary for germline specification. RNA-seq and ATAC-seq profiling reveal that Nanog acts as a barrier to prevent pluripotency transition, and autophagy-dependent Nanog degradation is important for dismantling the naive pluripotency expression program through decommissioning of naive-associated active enhancers. Mechanistically, we found that autophagy adaptor protein Sqstm1 (p62) is nucleus located during the pluripotency transition period and it is preferentially associated with ubiquitinated Nanog for selective protein degradation. In vivo, loss of autophagy by Atg7 depletion disrupts peri-implantation development and we observed increased chromatin association of Nanog, which affects neuronal differentiation through activation of a subset of neuroectodermal development-associated enhancers. Taken together, our findings illuminate regulatory mechanisms underlying the naive to primed transition and reveal that autophagy-dependent regulation of Nanog is essential for exit from the naive state and marks distinct cell fate allocation during lineage specification.
2020-05-30 | GSE151490 | GEO
Project description:Autophagy is a conserved cellular mechanism to degrade unwanted cytoplasmic proteins and organelles to recycle their components, and it is proved to be critical for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. However, the role of autophagy in embryonic development remains elusive, and no information exists regarding its functions during the transition from naive to primed pluripotency. Here by using an in vitro transition model of ESCs to epiblast-like cells (EpiLCs), we describe that the dynamic changes in Atg7-dependent autophagy is required for the naive to primed transition, and it is also necessary for germline specification. RNA-seq and ATAC-seq profiling reveal that Nanog acts as a barrier to prevent pluripotency transition, and autophagy-dependent Nanog degradation is important for dismantling the naive pluripotency expression program through decommissioning of naive-associated active enhancers. Mechanistically, we found that autophagy adaptor protein Sqstm1 (p62) is nucleus located during the pluripotency transition period and it is preferentially associated with ubiquitinated Nanog for selective protein degradation. In vivo, loss of autophagy by Atg7 depletion disrupts peri-implantation development and we observed increased chromatin association of Nanog, which affects neuronal differentiation through activation of a subset of neuroectodermal development-associated enhancers. Taken together, our findings illuminate regulatory mechanisms underlying the naive to primed transition and reveal that autophagy-dependent regulation of Nanog is essential for exit from the naive state and marks distinct cell fate allocation during lineage specification.
2020-05-20 | GSE150866 | GEO
Project description:Naive pluripotent cells in the implanting mouse blastocyst generate a rosette structure before undergoing lumenogenesis to form the egg cylinder. Simultaneously, they acquire primed pluripotency, the ability to differentiate into the primary germ layers. The existence of discrete intermediate pluripotent states during this transition has not been demonstrated. We identify here a distinct rosette pluripotent state, defined by co-expression of naive factors with transcription factor OTX2. Downregulation of WNT signals in the blastocyst drives transition into rosette pluripotency by inducing OTX2. The rosette then activates MEK signals that induce lumenogenesis and drive progression to primed pluripotency. Consequently, combined WNT and MEK inhibition supports rosette-like stem cells (RSCs), a self-renewing naive-primed intermediate. RSCs gain a unique epigenome that includes erasure of constitutive heterochromatin and bivalent marking of primed pluripotency genes. Notwithstanding this primed chromatin landscape, WNT induces reversion to naive pluripotency. The rosette is therefore a reversible pluripotent intermediate where control over pluripotency progression and morphogenesis pivots from WNT to MEK signals.
2020-04-28 | GSE105762 | GEO
Project description:Upon implantation, the naive pluripotent epiblast of the mouse blastocyst generates a rosette, undergoes lumenogenesis and forms the primed pluripotent egg cylinder, able to generate the embryonic tissues. How pluripotency progression and morphogenesis are linked, and whether intermediate pluripotent states exist remain controversial. We identify here a rosette pluripotent state, defined by co-expression of naive factors with transcription factor OTX2. Downregulation of blastocyst WNT signals drives transition into rosette pluripotency by inducing OTX2. The rosette then activates MEK signals that induce lumenogenesis and drive progression to primed pluripotency. Consequently, combined WNT and MEK inhibition supports rosette-like stem cells (RSCs), a self-renewing naive-primed intermediate. RSCs erase constitutive heterochromatin marks and display a primed chromatin landscape, with bivalently marked primed pluripotency genes. Nonetheless, WNT induces reversion to naive pluripotency. The rosette is therefore a reversible pluripotent intermediate where control over both pluripotency progression and morphogenesis pivots from WNT to MEK signals.
2020-04-28 | GSE112234 | GEO