Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA401733 | ENA |
REPOSITORIES: ENA
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Project description:Transcription factors drive Tet2-mediated enhancer demethylation to reprogram cell fate
| PRJNA401421 | ENA
Project description:Background: Aberrant DNA methylation is an epigenetic hallmark of most malignant tumors including breast cancer. However, the exact role of TET2-mediated DNA demethylation in ERα-positive luminal breast cancer is not well understood. Results: Here we showed by TCGA analyses that lower TET2 mRNA expression level is associated with worse clinical outcomes (i.e., overall survival) in ERα-positive but not ERα-negative breast cancer. Moreover, depletion of TET2 by CRISPR/Cas9 results in increased tumorigenesis capability of MCF7 cells in vitro. Whole genome bisulfite sequencing (WGBS) analysis revealed that DNA hypermethylation (gain-of-5mC) occurs within a subgroup of enhancers including estrogen responsive element (EREs) in MCF7 cells upon TET2 depletion. ChIP-seq and RNA-seq analysis showed that TET2 depletion impairs E2-induced ERα binding to these ‘gain-of-5mC’ EREs and gene transcription. Conclusions: Our data suggest that TET2-mediated enhancer DNA demethylation fine-tunes ERα-dependent and independent gene transcription in ERα-positive breast cancer cells.
2020-07-09 | GSE136673 | GEO
Project description:In mammals, cytosine methylation (5mC) is widely distributed throughout the genome but is notably depleted from active promoters and enhancers. While the role of DNA methylation in promoter silencing has been well documented, the function of this epigenetic mark at enhancers remains unclear. Recent experiments have demonstrated that enhancers are enriched for 5-hydroxymethylcytosine (5hmC), an oxidization product of the Tet family of 5mC dioxygenases and an intermediate of DNA demethylation. These results support the involvement of Tet proteins in the regulation of dynamic DNA methylation at enhancers. By mapping DNA methylation and hydroxymethylation at base resolution, we find that deletion of Tet2 causes extensive loss of 5hmC at enhancers, accompanied by enhancer hypermethylation, reduction of enhancer activity, and delayed gene induction in the early steps of differentiation. Our results reveal that DNA demethylation modulates enhancer activity, and its disruption influences the timing of transcriptome reprogramming during cellular differentiation. We performed traditional bisulfite sequencing, TAB-Seq, RNA-Seq, and ChIP-Seq for 6 histone modifications in two biological replicates of wild-type, Tet1-/-, and Tet2-/- mouse ES cells. We also performed RNA-Seq analysis during a timecourse of differentiation to neural progenitor cells.
2014-09-25 | E-GEOD-48519 | biostudies-arrayexpress
Project description:T cell function is regulated by epigenetic mechanisms. 5-methylcytosine (5mC) conversion to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (Tet) proteins was identified to mediate DNA demethylation. Here, we characterize the genome-wide distribution of 5hmC in T cells using DNA immunoprecipitation coupled with high-throughput DNA sequencing. 5hmC marks signature genes associated with effector cell differentiation in the putative regulatory elements. Moreover, Tet2 protein is recruited to 5hmC-containing regions, dependent on lineage-specific transcription factors. Deletion of the Tet2 gene in T cells decreased their cytokine expression, associated with reduced p300 recruitment. In vivo, Tet2 plays a critical role in the expression of cytokine genes. Collectively, our findings for the first time demonstrate a key role of Tet-mediated active DNA demethylation in T cells. A total of 8 samples were analyzed. The expression patterns in Tet2 wild-type and deficient Th1 and Th17 cells were analyzed.
2015-04-12 | E-GEOD-66944 | biostudies-arrayexpress
Project description:DNA methylation plays critical roles in regulating muscle cell fate determination and myogenesis. Tet dioxygenases are responsible for active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2 is required for complete regeneration after muscle injury. Loss of Tet2 in myoblasts leads to reduced fusion index and thinner myofibers. Tet2 activates transcription of key differentiation modulator Myogenin (MyoG) further promoting myoblast differentiation and fusion. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 facilitates the recruitment of H3K4me1 and H3K27ac, increases the chromatin accessibility, and MyoD binding on MyoG enhancer. These functions are specifically executed by Tet2, but not Tet1 and Tet3. We identified the Tet2 specific function during myogenesis and shed new lights on DNA methylation and pioneer transcription factor transcription activation.
2021-06-01 | GSE158646 | GEO
Project description:DNA methylation plays critical roles in regulating muscle cell fate determination and myogenesis. Tet dioxygenases are responsible for active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2 is required for complete regeneration after muscle injury. Loss of Tet2 in myoblasts leads to reduced fusion index and thinner myofibers. Tet2 activates transcription of key differentiation modulator Myogenin (MyoG) further promoting myoblast differentiation and fusion. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 facilitates the recruitment of H3K4me1 and H3K27ac, increases the chromatin accessibility, and MyoD binding on MyoG enhancer. These functions are specifically executed by Tet2, but not Tet1 and Tet3. We identified the Tet2 specific function during myogenesis and shed new lights on DNA methylation and pioneer transcription factor transcription activation.
2021-06-01 | GSE158648 | GEO
Project description:DNA methylation plays critical roles in regulating muscle cell fate determination and myogenesis. Tet dioxygenases are responsible for active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2 is required for complete regeneration after muscle injury. Loss of Tet2 in myoblasts leads to reduced fusion index and thinner myofibers. Tet2 activates transcription of key differentiation modulator Myogenin (MyoG) further promoting myoblast differentiation and fusion. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 facilitates the recruitment of H3K4me1 and H3K27ac, increases the chromatin accessibility, and MyoD binding on MyoG enhancer. These functions are specifically executed by Tet2, but not Tet1 and Tet3. We identified the Tet2 specific function during myogenesis and shed new lights on DNA methylation and pioneer transcription factor transcription activation.
2021-06-01 | GSE158647 | GEO
Project description:The mechanisms whereby the crucial pluripotency transcription factor Oct4 regulates target gene expression are incompletely understood. Using an assay system based on partially differentiated embryonic stem cells, we show that Oct4 opposes accumulation of local H3K9me2, and subsequent Dnmt3a-mediated DNA methylation. Upon binding DNA, Oct4 recruits the histone lysine demethylase Jmjd1c. ChIP timecourse experiments identify a stepwise Oct4 mechanism involving Jmjd1c recruitment and H3K9me2 demethylation, transient FACT complex recruitment, and nucleosome depletion. Genome-wide and targeted ChIP confirms binding of newly-synthesized Oct4, together with Jmjd1c and FACT, to the Pou5f1 enhancer and a small number of other Oct4 targets, including the Nanog promoter. Histone demethylation is required for both FACT recruitment and H3 depletion. Jmjd1c is required to induce endogenous Oct4 expression and fully reprogram fibroblasts to pluripotency, indicating that the assay system identifies functional Oct4 cofactors. These findings indicate that Oct4 sequentially recruits activities that catalyze histone demethylation and depletion. Examination of transcription factor occupancy in cells with newly synthesized Oct4.
2015-01-23 | E-GEOD-65192 | biostudies-arrayexpress
Project description:Tet2-mediated demethylation is a key component of epigenetic programing that promotes lineage specific gene expression and contributes to cellular differentiation and function. While the differentiation of CD4+ T cell subsets has been studied extensively, the epigenetic programs that regulate these processes remain unclear. We report that Tet2 acts to restrict the differentiation of T follicular helper (Tfh) cells in CD4+ T cells responding to viral infection. Tet2-deficient CD4+ T cells preferentially differentiated into highly functional germinal center (GC) Tfh cells that provided enhanced help for B cell responses. Using genome-wide expression and methylation analyses combined with Foxo1 ChIPseq analysis, we found that Tet2 coordinates with multiple transcription factors, including Foxo1, to mediate the demethylation and expression of their target genes following activation.
2022-06-15 | GSE183316 | GEO
Project description:Tet2-mediated demethylation is a key component of epigenetic programing that promotes lineage specific gene expression and contributes to cellular differentiation and function. While the differentiation of CD4+ T cell subsets has been studied extensively, the epigenetic programs that regulate these processes remain unclear. We report that Tet2 acts to restrict the differentiation of T follicular helper (Tfh) cells in CD4+ T cells responding to viral infection. Tet2-deficient CD4+ T cells preferentially differentiated into highly functional germinal center (GC) Tfh cells that provided enhanced help for B cell responses. Using genome-wide expression and methylation analyses combined with Foxo1 ChIPseq analysis, we found that Tet2 coordinates with multiple transcription factors, including Foxo1, to mediate the demethylation and expression of their target genes following activation.
2022-06-15 | GSE183315 | GEO