TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells
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ABSTRACT:
PROVIDER: PRJNA329247 | ENA |
REPOSITORIES: ENA
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Project description:TET enzymes oxidise DNA methylation as part of an active demethylation pathway. Despite extensive research into the role of TETs in genome regulation, little is known about their effect on transposable elements (TEs), which make up nearly half of the mouse and human genomes. Epigenetic mechanisms controlling TEs have the potential to affect their mobility and to drive the co-adoption of TEs for the benefit of the host. We have performed a detailed investigation of the role of TET enzymes in the regulation of TEs in mouse embryonic stem cells (ESCs). We found that TET1 and TET2 bind multiple TE classes that harbour a variety of epigenetic signatures indicative of different functional roles. Namely, TETs co-bind with pluripotency factors to enhancer-like TEs that interact with highly expressed genes in ESCs, whose expression is partly maintained by the demethylating action of TET2. TETs and 5-hydroxymethylcytosine are also strongly enriched at the 5’ UTR of full-length, evolutionarily young LINE1 elements, a pattern that is conserved in human embryonic stem cells. TET depletion leads to a marked increase in DNA methylation levels at LINE1s, but surprisingly their expression is stably maintained through additional TET-dependent activities. Specifically, we find that TET1 recruits the SIN3A co-repressive complex to LINE1s, ensuring their repression upon TET-driven hypomethylation. This dual nature of TET action may reflect the evolutionary battle between TEs and the host. Our data implicate TET enzymes in the evolutionary dynamics of TEs, both in the context of exaptation processes and of retrotransposition control.
2016-10-28 | GSE84458 | GEO
Project description:TET enzymes oxidise DNA methylation as part of an active demethylation pathway. Despite extensive research into the role of TETs in genome regulation, little is known about their effect on transposable elements (TEs), which make up nearly half of the mouse and human genomes. Epigenetic mechanisms controlling TEs have the potential to affect their mobility and to drive the co-adoption of TEs for the benefit of the host. We have performed a detailed investigation of the role of TET enzymes in the regulation of TEs in mouse embryonic stem cells (ESCs). We found that TET1 and TET2 bind multiple TE classes that harbour a variety of epigenetic signatures indicative of different functional roles. Namely, TETs co-bind with pluripotency factors to enhancer-like TEs that interact with highly expressed genes in ESCs, whose expression is partly maintained by the demethylating action of TET2. TETs and 5-hydroxymethylcytosine are also strongly enriched at the 5’ UTR of full-length, evolutionarily young LINE1 elements, a pattern that is conserved in human embryonic stem cells. TET depletion leads to a marked increase in DNA methylation levels at LINE1s, but surprisingly their expression is stably maintained through additional TET-dependent activities. Specifically, we find that TET1 recruits the SIN3A co-repressive complex to LINE1s, ensuring their repression upon TET-driven hypomethylation. This dual nature of TET action may reflect the evolutionary battle between TEs and the host. Our data implicate TET enzymes in the evolutionary dynamics of TEs, both in the context of exaptation processes and of retrotransposition control.
2016-10-28 | GSE84459 | GEO
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
Project description: Not available
| S-EPMC5116139 | biostudies-literature
Project description:TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells [RNA-seq]
| PRJNA329257 | ENA
Project description:TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells [small RNA-seq]
| PRJNA329256 | ENA
Project description:In this study we have examined the role of Tet enzymes in regulation of embryonic Endothelial cells (ECs) and Hematopoietic stem and progenitor cells (HSPCs). We have performed transcriptomic and methylation analyses of Tet deficient and wild type ECs and HSPCs isolated from E11.5 embryonic aorta-gonad-mesonephros (AGM) to identify differentially expressed genes and differentially methylated regions.
2022-02-19 | GSE176391 | GEO
Project description:We generated tetracycline-inducible myc-GABPα-expressing Gabpα conditional knockout embryonic stem cells (Tet-Gabbpα cKO ES cells), and then compared the transcriptional profiles between control (-Tet) and Gabpα-null (+Tet) cells by an oligo DNA microarray analysis.
2017-07-01 | GSE82231 | GEO
Project description:Tet enzymes (Tet1/2/3) catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC) and are dynamically expressed in various embryonic and adult cell types. While loss of individual Tet enzymes or combined deficiency of Tet1/2 allows for embryogenesis, the effect of complete loss of Tet activity and 5hmC marks in development has not been established. To define the role of Tet enzymes and 5hmC in development we have generated Tet1, Tet2 and Tet3 triple knockout (TKO) mouse embryonic stem cells (ESCs) and examined their developmental potential in vitro and in vivo. Combined deficiency of all three Tet enzymes led to complete depletion of 5hmC and impaired ESC differentiation as seen in poorly differentiated TKO embryoid bodies and teratomas. Consistent with impaired differentiation, TKO ES cells exhibited limited contribution to the chimeric embryos and could not support embryonic development in tetraploid complementation assays. Gene expression profiles and genome wide methylome analyses of TKO embryoid bodies revealed promoter hypermethylation and deregulation of genes implicated in embryonic development and differentiation. These findings suggest a requirement for Tet and 5hmC-mediated DNA demethylation in proper regulation of gene expression during differentiation of embryonic stem cells and development.
2014-04-17 | GSE55049 | GEO
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 | GSE221469 | GEO