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TET1 is a maintenance DNA demethylase that prevents methylation spreading in adult cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: CHUNLEI JIN

PROVIDER: E-GEOD-44039 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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TET1 is a maintenance DNA demethylase that prevents methylation spreading in differentiated cells.

Jin Chunlei C Lu Yue Y Jelinek Jaroslav J Liang Shoudan S Estecio Marcos R H MR Barton Michelle Craig MC Issa Jean-Pierre J JP

Nucleic acids research 20140529 11

TET1 is a 5-methylcytosine dioxygenase and its DNA demethylating activity has been implicated in pluripotency and reprogramming. However, the precise role of TET1 in DNA methylation regulation outside of developmental reprogramming is still unclear. Here, we show that overexpression of the TET1 catalytic domain but not full length TET1 (TET1-FL) induces massive global DNA demethylation in differentiated cells. Genome-wide mapping reveals that 5-hydroxymethylcytosine production by TET1-FL is inhi ...[more]

PMID: 24875481

Similar Datasets

TET1 is a maintenance DNA demethylase that prevents methylation spreading in adult cells [MeDIP-Seq]

2014-06-04 | E-GEOD-44036 | biostudies-arrayexpress

TET1 is a maintenance DNA demethylase that prevents methylation spreading in adult cells [DREAM]

Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. Digital restriction enzyme analysis of methylation (DREAM) was performed to determine the DNA methylation profiles of HEK293T cells overexpressing mTET1-CD, TET1-CD, mTET1-FL, or TET1-FL. In this approach, genomic DNA is sequentially cut at CCCGGG sites with the methylation sensitive enzyme SmaI (blunt ends) and its methylation-tolerant neoschizomer XmaI (5M-bM-^@M-^YCCGG overhangs), creating different end sequences that represent methylation status of the CCCGGG sites. These end sequences are analyzed by next generation sequencing, and thereafter the methylation status at individual CCCGGG sites across the genome can be determined.

2014-06-04 | E-GEOD-44038 | biostudies-arrayexpress

TET1 is a maintenance DNA demethylase that prevents methylation spreading in adult cells [RNA-seq]

2014-06-04 | E-GEOD-49833 | biostudies-arrayexpress

TET1 is a maintenance DNA demethylase that prevents methylation spreading in adult cells [cDNA microarray]

Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. HEK293T cells were transfected with wild type or catalytically mutant TET1 expression plasmids (TET1-CD, mTET1-CD, TET1-FL and mTET1-FL), or subjected to shRNA-mediated TET1 knockdown. Total RNA samples were extracted and assayed on Affymetrix microarrays

2014-06-04 | E-GEOD-50016 | biostudies-arrayexpress

Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity

Project description:This SuperSeries is composed of the following subset Series: GSE34886: Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity [expression profiling] GSE34887: Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity [MRE-seq] Refer to individual Series

2012-01-04 | E-GEOD-34267 | biostudies-arrayexpress

Tet1 and hydroxymethylcytosine in transcription and DNA methylation fidelity

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2011-04-13 | E-GEOD-24843 | biostudies-arrayexpress

Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity [MRE-seq]

Project description:The TET family of FE(II) and 2-oxoglutarate-dependent enzymes (Tet1/2/3) promote DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), which they further oxidize into 5-formylcytosine and 5-carboxylcytosine. Tet1 is robustly expressed in mouse embryonic stem cells (mESCs) and has been implicated in mESC maintenance. Here we demonstrate that, unlike genetic deletion, RNAi-mediated depletion of Tet1 in mESCs led to a significant reduction in 5hmC and loss of mESC identity. The differentiation phenotype due to Tet1 depletion positively correlated with the extent of 5hmC loss. Meta-analyses of genomic datasets suggested interaction between Tet1 and leukemia inhibitory factor (LIF) signaling. LIF signaling is known to promote self-renewal and pluripo-tency in mESCs partly by opposing MAPK/ERK mediated differentiation. Withdrawal of LIF leads to differentiation of mESCs. We discovered that Tet1 depletion impaired LIF-dependent Stat3-mediated gene activation by affecting Stat3's ability to bind to its target sites on chromatin. Nanog overexpression or inhibition of MAPK/ERK signaling, both known to maintain mESCs in the absence of LIF, rescued Tet1 depletion, further supporting the dependence of LIF/Stat3 signaling on Tet1. These data support the conclusion that analysis of mESCs in the hours/days immediately following efficient Tet1 depletion reveals Tet1’s normal physiological role in maintaining the pluripotent state that may be subject to homeostatic compensation in genetic models. Genome-wide mapping of 5hmC and microarray gene expression profiling in E14Tg2a mESCs after transfection with indicated siRNAs: Tet1 siRNA #1 (Invitrogen, MSS284895), Tet1 siRNA #2 (Invitrogen, MSS284897), and Control siRNA duplex targeting firefly luciferase.

2012-01-06 | E-GEOD-34887 | biostudies-arrayexpress

Genome-wide Regulation of 5hmC, 5mC and Gene Expression by Tet1 Hydroxylase in Mouse Embryonic Stem Cells (expression data)

Project description:DNA methylation of C5-cytosine (5mC) in the mammalian genome is a key epigenetic event that is critical for various cellular processes. However, how the genome-wide 5mC pattern is dynamically regulated remains a fundamental question in epigenetic biology. The TET family of 5mC hydroxylases, which convert 5mC to 5-hydroxymethylcytosine (5hmC), have provided a new potential mechanism for the dynamic regulation of DNA methylation. The extent to which individual Tet family members contribute to the genome-wide 5mC and 5hmC patterns and associated gene network remains largely unknown. Here we report genome-wide mapping of Tet1 and 5hmC in mESCs and reveal a mechanism of action by which Tet1 controls 5hmC and 5mC levels in mESCs. In combination with microarray and mRNA-seq expression profiling, we identify a comprehensive yet intricate gene network influenced by Tet1. We propose a model whereby Tet1 controls DNA methylation both by binding to CpG-rich regions to prevent unwanted DNA methyltransferase activity, and by converting the existing 5mC to 5hmC through its enzymatic activity. This Tet1-mediated antagonism of CpG methylation imparts differential maintenance of DNA methylation status at Tet1 target loci, thereby providing a new regulatory mechanism for establishing the epigenetic landscape of mESCs, which ultimately contributes to mESC differentiation and the onset of embryonic development. Tet1 protein was depleted in J1 or E14 mouse ES cells by siRNA or shRNA treatment. Total RNA was purified and used to determine the global gene transcription profiles by microarray assays. The Tet1-regulated genes were identified by comparing the gene expression profiles of control and Tet1-depleted ES cells.

2011-04-21 | E-GEOD-28530 | biostudies-arrayexpress

Tet1 and hydroxymethylcytosine in transcription and DNA methylation fidelity (ChIP/DIP-Seq data)

Project description:We analyzed the genome-wide binding of Tet1 in control (shScr) and Tet1 knockdown (shTet1) mouse ES cells using two different Tet1 antibodies (Tet1-C and Tet1-N). Furthermore, we generated genome-wide mapping of hydroxymethyl cytosine (hmC) and methyl cytosine (mC). We find that hmC, in contrast to mC, is also found at transcription start sites (TSSs), and that there is a significant overlap between Tet1 binding and hmC positive regions. Surprisingly, our results also suggest, that Tet1 has a role in transcriptional repression. We showed that Tet1 associates with Sin3A co-repressor complex, and by performing ChIP-sequencing of Sin3A, we find co-localisation of Tet1 and Sin3a throughout the genome Examination of Tet1 and Sin3A binding as well as hmC and mC localization in mouse ES cells

2011-04-13 | E-GEOD-24841 | biostudies-arrayexpress

RNAseq analyses in HEK293T-ACE2 cells infected with SARS-CoV-2 (VOC Delta, 24hours) vs untreated cells

Project description:In this study a gene expression (i.e., RNAseq) analysis was performed in HEK293T-ACE2 cellular model upon infection with viral particle belonging to VOC Delta (MOI: 0.026) for 24 hours in order to have a global picture of the transcriptome landscape in response to early phase of infection of SARS-CoV-2 ( VOC Delta infection and to evaluate the role of Ca2+ in HEK293-ACE2 cellular model and transfer to homeostasis in SARS-COV-2 patients (by Pasqualino de Antonellis1-2* and Veronica Ferrucci 1-2* (first authors) et al. and Massimo Zollo1-2# (corresponding author). Manuscript in preparation 2022 July 15th 2022. Short title "ATP2B1 (PMCA1), regulated by FOXO3, influences susceptibility to severe COVID19".

2022-12-01 | E-MTAB-11973 | biostudies-arrayexpress

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