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Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (DNase-seq)

ABSTRACT: Naïve mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping, we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naïve-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naïve pluripotency to a somatic regulatory program.

ORGANISM(S): Mus musculus

PROVIDER: GSE57406 | GEO | 2014/06/04

SECONDARY ACCESSION(S): PRJNA246399

REPOSITORIES: GEO

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Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (ChIP-seq)

Project description:Naïve mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping, we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naïve-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naïve pluripotency to a somatic regulatory program.

2014-06-04 | GSE57407 | GEO

Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (RNA-seq)

2014-06-04 | GSE57403 | GEO

Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (DNase-seq)

Project description:NaM-CM-/ve mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping, we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naM-CM-/ve-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naM-CM-/ve pluripotency to a somatic regulatory program. DNase sequencing of histone modifications in mouse epiblast stem cells

2014-06-04 | E-GEOD-57406 | biostudies-arrayexpress

Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (ChIP-seq)

Project description:NaM-CM-/ve mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping, we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naM-CM-/ve-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naM-CM-/ve pluripotency to a somatic regulatory program. ChIP sequencing of histone modifications in mouse epiblast stem cells

2014-06-04 | E-GEOD-57407 | biostudies-arrayexpress

Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (RNA-seq)

Project description:NaM-CM-/ve mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping, we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naM-CM-/ve-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naM-CM-/ve pluripotency to a somatic regulatory program. RNA sequencing in quadruplicate of mouse embryonic stem cells and epiblast stem cells

2014-06-04 | E-GEOD-57403 | biostudies-arrayexpress

Novel culture conditions facilitating the induction of naïve pluripotency in human embryonic stem cells

Project description:It is now well recognized that human embryonic stem cells (hESCs)1 closely resemble mouse epiblast stem cells (mEpiSCs)2-5 exhibiting primed pluripotency unlike mouse ESCs (mESCs) which acquire a naïve pluripotent state4-8. Efforts have been made to trigger naïve pluripotency in hESCs9-11 for subsequent unbiased lineage-specific differentiation, a common conundrum faced by primed pluripotent hESCs due to heterogeneity in gene expression existing within and between hESC lines12. We report here a novel culture medium facilitating rapid induction of naïve pluripotency in established hESCs. Our medium also allows derivation of naïve mESCs from blastocyst stage which has not been shown earlier. The established naïve hESCs could survive long-term single cell passaging, maintain a normal karyotype, exhibit upregulation of naïve pluripotency genes and were dependent on signaling pathways similar to naïve mESCs. Also, they undergo global DNA demethylation, cluster together with previously described naïve hESCs13 and show a distinctive long non-coding RNA profile. Collectively, we demonstrate an alternate route to capture naïve pluripotency in hESCs which is fast, reproducible, can be employed to derive naïve mESCs and can induce efficient differentiation. Three primed and matching naive human embryonic stem cell lines were profiled in duplo.

2015-06-08 | E-GEOD-57271 | biostudies-arrayexpress

Novel culture conditions facilitating the induction of naïve pluripotency in human embryonic stem cells

2015-06-08 | GSE57271 | GEO

Activin A in Combination with ERK1/2 MAPK Pathway Inhibition Sustains Propagation of Mouse Embryonic Stem Cells

Project description:Activin/Nodal/TGF-β signaling pathway plays a major role in maintaining mouse epiblast stem cells (mEpiSCs). The mEpiSC medium which contains Activin A and bFGF induces differentiation of mouse embryonic stem cells (mESCs) to mEpiSC. Here we show that Activin A also has an ability to efficiently propagate mESCs without differentiation to mEpiSCs when combined with a MEK inhibitor PD0325901. mESCs cultured in Activin+PD retained high-level expression of naive pluripotency-related transcription factors. Genome-wide analysis revealed that the gene expression profile of mESCs cultured in Activin+PD resembles that of mESCs cultured in 2i. mESCs cultured in Activin+PD also showed features which are related to naive pluripotency of mESCs, including the preferential usage of the Oct4 distal enhancer and the self-renewal response to Wnt pathway activation. Our finding reveals a role of Activin/Nodal/TGF-β signaling in stabilizing self-renewal gene regulatory networks in mESCs. To compare the gene expression patterns of mESCs cultured in Activin+PD, 2i and LIF+BMP4 and mEpiSCs, we performed genome-wide gene expression analysis by using Affymetrix GeneChip oligonucleotide microarrays

2019-07-11 | GSE84679 | GEO

AMPK activation reverts mouse epiblast stem cells to naïve state

Project description:Reversion from primed to naïve pluripotent status has been achieved by various signaling manipulation, but it is still unclear what signaling is the actual driving force to get over the hurdle from primed to naïve pluripotency. We previously reported that activation of AMP kinase (AMPK) contributed to maintenance of naïve pluripotency. Here, we further show that AMPK activators, AICAR, A769662 or metformin, can induce the reversion of primed mouse epiblast stem cells (mEpiSCs) to naïve pluripotent state. Primed mEpiSCs in our naïve cell culture condition with leukemia inhibitory factor (LIF) and 2 kinase inhibitors (2i) (2iL) never gave rise to naïve state cells. Addition of AICAR alone even in the absence of 2iL or either of AMPK inhibitors with LIF induced appearance of naïve-like cells from primed mEpiSCs. Through maintenance and passages of these cells in 2iL condition, clear naïve-like morphology colonies were purely obtained. They showed core naïve protein expression, and global naïve gene expression profiles. These cells contributed to chimeric mice including germline transmission. Inhibition of p38 signaling abolished the AMPK-elicited reversion and forced activation of p38 in primed mEpiSCs partially reproduced the naïve cell induction, suggesting that p38 is one of the critical downstream in AMPK activation. AMPK pathway should be a novel critical driving force in reversion of primed to naïve pluripotency.

2021-07-21 | GSE157087 | GEO

AMPK activation reverts mouse epiblast stem cells to naïve state

Project description:Reversion from primed to naïve pluripotent status has been achieved by various signaling manipulation, but it is still unclear what signaling is the actual driving force to get over the hurdle from primed to naïve pluripotency. We previously reported that activation of AMP kinase (AMPK) contributed to maintenance of naïve pluripotency. Here, we further show that AMPK activators, AICAR, A769662 or metformin, can induce the reversion of primed mouse epiblast stem cells (mEpiSCs) to naïve pluripotent state. Primed mEpiSCs in our naïve cell culture condition with leukemia inhibitory factor (LIF) and 2 kinase inhibitors (2i) (2iL) never gave rise to naïve state cells. Addition of AICAR alone even in the absence of 2iL or either of AMPK inhibitors with LIF induced appearance of naïve-like cells from primed mEpiSCs. Through maintenance and passages of these cells in 2iL condition, clear naïve-like morphology colonies were purely obtained. They showed core naïve protein expression, and global naïve gene expression profiles. These cells contributed to chimeric mice including germline transmission. Inhibition of p38 signaling abolished the AMPK-elicited reversion and forced activation of p38 in primed mEpiSCs partially reproduced the naïve cell induction, suggesting that p38 is one of the critical downstream in AMPK activation. Single cell RNA-seq analysis under AICAR stimulation successfully demonstrated the reversion process with appearance of intermediate naïve-like population. AMPK pathway should be a novel critical driving force in reversion of primed to naïve pluripotency.

2021-07-21 | GSE175610 | GEO

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