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TET activity propagates transcriptional memory through embryonic dormancy [RNA-Seq]

ABSTRACT: Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus under dormancy, which can be induced in vitro through mTOR inhibition. Dormancy features silencing of the genome and abundant heterochromatin formation, which conflicts with the permissive and uncommitted genomic profile of pluripotent cells. Cellular strategies to maintain pluripotency in the fate of this conflict are not known. Here we probed chromatin regulation during embryonic stem cells’ (ESC) entry into dormancy to identify mechanisms that ensure nsure faithful propagation of cellular identity through dormancy. We show a global increase in DNA methylation and loss of chromatin accessibility in dormant ESCs and find that TET DNA demethylases are essential to counteract this trend at key pluripotency regulatory elements. Perturbation of TET activity compromises transcriptional programs and embryo survival through dormancy; whereas its enhancement improves survival rates. We propose that key regulatory elements are bookmarked coordinately by TETs and transcription factors in dormancy for maintenance of cellular identity. Our results reveal the first essential chromatin regulator in establishing mammalian dormancy and paves the way to building its temporal regulatory code in embryonic and adult tissues.

ORGANISM(S): Mus musculus

PROVIDER: GSE221467 | GEO | 2024/03/19

REPOSITORIES: GEO

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TET activity propagates transcriptional memory through embryonic dormancy [FLASH - RNA-Seq]

Project description:Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus under dormancy, which can be induced in vitro through mTOR inhibition. Dormancy features silencing of the genome and abundant heterochromatin formation, which conflicts with the permissive and uncommitted genomic profile of pluripotent cells. Cellular strategies to maintain pluripotency in the fate of this conflict are not known. Here we probed chromatin regulation during embryonic stem cells’ (ESC) entry into dormancy to identify mechanisms that ensure nsure faithful propagation of cellular identity through dormancy. We show a global increase in DNA methylation and loss of chromatin accessibility in dormant ESCs and find that TET DNA demethylases are essential to counteract this trend at key pluripotency regulatory elements. Perturbation of TET activity compromises transcriptional programs and embryo survival through dormancy; whereas its enhancement improves survival rates. We propose that key regulatory elements are bookmarked coordinately by TETs and transcription factors in dormancy for maintenance of cellular identity. Our results reveal the first essential chromatin regulator in establishing mammalian dormancy and paves the way to building its temporal regulatory code in embryonic and adult tissues.

2024-03-19 | GSE221468 | GEO

TET activity propagates transcriptional memory through embryonic dormancy [CUT&Tag]

2024-03-19 | GSE221466 | GEO

TET activity propagates transcriptional memory through embryonic dormancy [WGBS]

2024-03-19 | GSE221469 | GEO

TET activity propagates transcriptional memory through embryonic dormancy [ATAC-Seq]

2024-03-19 | GSE221465 | GEO

TET activity propagates transcriptional memory through embryonic dormancy [CUT&TAG]

2024-03-19 | GSE245230 | GEO

TET activity propagates transcriptional memory through embryonic dormancy [RNA-seq]

2024-03-19 | GSE245229 | GEO

TET activity propagates transcriptional memory through embryonic dormancy

Project description:Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus under dormancy, which can be induced in vitro through mTOR inhibition. Dormancy features silencing of the genome and abundant heterochromatin formation, which conflicts with the permissive and uncommitted genomic profile of pluripotent cells. Cellular strategies to maintain pluripotency in the fate of this conflict are not known. Here we probed chromatin regulation during embryonic stem cells’ (ESC) entry into dormancy to identify mechanisms that ensure faithful propagation of cellular identity through dormancy. We show a global increase in DNA methylation and loss of chromatin accessibility in dormant ESCs and find that TET DNA demethylases are essential to counteract this trend at key pluripotency regulatory elements, particularly at young LINE1 repeats and active enhancers. Demethylation of these targets by TETs is essential for transcription factor (TF) recruitment and transient chromatin decondensation before hypercompaction. We propose that key regulatory elements are bookmarked coordinately by TETs and TFs in dormancy for maintenance of cellular identity. Perturbation of TET activity compromises embryo survival through dormancy; whereas its enhancement improves survival rates. Our results reveal the first essential chromatin regulator in establishing mammalian embryonic dormancy and pave the way to building its temporal regulatory code in embryonic and adult tissues.

2024-03-22 | PXD039056 | Pride

AKT signaling promotes epigenetic reprogramming via upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation.

Project description:Phosphoinositide-3 kinase (PI3K)/AKT signaling participates in cellular proliferation, survival, and tumorigenesis as well as cellular reprogramming including generation of induced pluripotent stem cells (iPSCs). In this study, we revealed that activation of AKT in somatic cells undergoing reprogramming enhances epigenetic reprogramming. Activated AKT in reprogramming cells triggers elevated anabolic glucose metabolism, and, accordingly, increases the level of α-ketoglutarate (αKG) which is an essential cofactor for the enzymatic activity of the 5-methylcytosine (5mC) dioxygenase TET. Additionally, the level of TET was upregulated. Consistent with upregulated KG production and TET, we observed a genome-wide increase in 5-hydorxymethylcytosine (5hmC) which is an intermediate in the DNA demethylation process. Moreover, DNA methylation level at ES-cell super-enhancers of pluripotency-related genes was significantly decreased, leading upregulation of associated genes. Taken together, our results indicate that AKT signaling is associated with epigenetic regulation by hyperactivating TET at catalytical and transcriptional levels during the somatic cell reprogramming.

2021-09-29 | GSE161344 | GEO

AKT signaling promotes epigenetic reprogramming via upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation

Project description:Phosphoinositide-3 kinase (PI3K)/AKT signaling participates in cellular proliferation, survival, and tumorigenesis as well as cellular reprogramming including generation of induced pluripotent stem cells (iPSCs). In this study, we revealed that activation of AKT in somatic cells undergoing reprogramming enhances epigenetic reprogramming. Activated AKT in reprogramming cells triggers elevated anabolic glucose metabolism, and, accordingly, increases the level of α-ketoglutarate (αKG) which is an essential cofactor for the enzymatic activity of the 5-methylcytosine (5mC) dioxygenase TET. Additionally, the level of TET was upregulated. Consistent with upregulated KG production and TET, we observed a genome-wide increase in 5-hydorxymethylcytosine (5hmC) which is an intermediate in the DNA demethylation process. Moreover, DNA methylation level at ES-cell super-enhancers of pluripotency-related genes was significantly decreased, leading upregulation of associated genes. Taken together, our results indicate that AKT signaling is associated with epigenetic regulation by hyperactivating TET at catalytical and transcriptional levels during the somatic cell reprogramming.

2021-09-29 | GSE161399 | GEO

Stirred suspension bioreactors maintain naïve pluripotency of human pluripotent stem cells (hPSCs)

Project description:Although cell therapies require large numbers of quality-controlled hPSCs, existing technologies are limited in their ability to efficiently grow and scale stem cells. We report here that cell-state conversion from primed-to-naïve pluripotency enhances the biomanufacturing of hPSCs. Naïve hPSCs exhibit superior growth kinetics and aggregate formation characteristics in stirred suspension bioreactors compared to their primed counterparts. Moreover, we demonstrate the role of the bioreactor mechanical environment in the maintenance of naïve pluripotency, through transcriptomic enrichment of mechano-sensing signaling for cells in the bioreactor along with a decrease in expression of lineage-specific and primed pluripotency hallmarks. Bioreactor-cultured, naïve hPSCs express epigenetic regulatory transcripts associated with naïve pluripotency, and display hallmarks of X-chromosome reactivation. They exhibit robust production of naïve pluripotency metabolites and display reduced expression of primed pluripotency cell surface markers. We also show that these cells retain the ability to undergo targeted differentiation into beating cardiomyocytes, hepatocytes, and neural rosettes. They additionally display faster kinetics of teratoma formation compared to their primed counterparts. Naïve bioreactor hPSCs also retain structurally stable chromosomes. Our research corroborates that converting hPSCs to the naïve state enhances hPSC manufacturing and indicates a potentially important role for the bioreactor’s mechanical environment in maintaining naïve pluripotency.

2020-05-08 | ST001377 | MetabolomicsWorkbench

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