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TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells [TET2 ChIP-seq ES cells]

ABSTRACT: The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development, lead to altered DNA methylation landscapes and to an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed Acute Myeloid Leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix-loop-helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provide a compelling example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.

ORGANISM(S): Mus musculus

PROVIDER: GSE115964 | GEO | 2019/01/22

REPOSITORIES: GEO

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TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells [TET2 ChIP-seq hematopoietic cells]

Project description:The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development, lead to altered DNA methylation landscapes and to an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed Acute Myeloid Leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix-loop-helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provide a compelling example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.

2019-01-22 | GSE115965 | GEO

TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells [RNA-Seq]

2019-01-22 | GSE115967 | GEO

TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells [ATAC-Seq]

2019-01-22 | GSE115962 | GEO

TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells [TET2 ChIP-seq hematopoietic cells]

Project description:TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells [TET2 ChIP-seq hematopoietic cells]

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TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells [TET2 ChIP-seq ES cells]

Project description:TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells [TET2 ChIP-seq ES cells]

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TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

Project description:TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

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Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis (Affymetrix)

Project description:DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. Gene expression profiles from Tet2-/-;AML1-ETO and Tet2fl/fl;AML1-ETO in vitro-grown hematopoietic cells were compared using GeneChip Mouse Gene ST 2.0 Arrays (Affymetrix). Expression changes were investigated at early (passage 2) and late (passage 10) timepoints after Tet2 disruption.

2015-04-22 | E-GEOD-59586 | biostudies-arrayexpress

FLT3-ITD mutations and TET2 loss synergistically alter global DNA methylation in AML

Project description:Studies of AML patient samples have shown that specific combinations of AML disease alleles confer an adverse outcome, however, in vivo models do not exist for the majority of common, poor-prognosis genotypes. Here we show that TET2/FLT3 mutations can cooperate to induce AML in vivo using a genetically engineered mouse model, and that this model has a defined stem-cell population with a characteristic transcriptional and epigenetic profile. TET2 and FLT3 mutations cooperate to induce site-specific changes in DNA methylation and gene expression, including at loci that regulate hematopoietic differentiation. We demonstrate that re-expression of genes that are silenced in TET2/FLT3-mutant AML restores normal differentiation, demonstrating that the epigenetic program of TET2/FLT3-mutant AML cells can be reversed in vitro and in vivo. Using ERRBS, we profiled genome-wide DNA methylation patterns of the hematopoietic stem cells (LSK) population in Wide-type, Flt3-IDT, Tet2-/-, and Tet2-/-Flt3-IDT mice, each in triplicates

2015-04-14 | E-GEOD-57114 | biostudies-arrayexpress

TET2 is a component of the ER complex and controls 5mC to 5hmC conversion at ER cis-regulatory regions

Project description:Estrogen receptor-alpha (ER) drives tumour development and metastasis in ER positive (ER+) breast cancer. GATA3 is a transcription factor that has been closely linked to ER function, but the role of GATA3 in ER-transcriptional activity is not clear. We sought to identify the contribution of GATA3 to the ER complex, by conducting quantitative multiplexed rapid immunoprecipitation mass spectrometry of endogenous proteins (qPLEX-RIME), to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, very few proteins were dissociated from the ER complex in the absence of GATA3, with the only major change being loss of TET2 in the ER complex. In breast cancer cells and Patient-Derived Xenograft (PDX) tissue, TET2 binding events were shown to constitute a near-total subset of ER binding events, and loss of TET2 was functionally associated with reduced activation of proliferative pathways. To investigate the TET2-ER relationship, the role of TET2 in regulating DNA modifications in ER+ breast cancer cells was examined. TET2 knockdown did not appear to result in changes to global DNA methylation, however, oxidation of methylated DNA to 5-hydroxymethylcytosine (5hmC) was significantly reduced after TET2 depletion and these events occurred at ER enhancers. These findings implicate TET2 in the production and maintenance of 5hmC at ER sites, providing a potential mechanism for TET2-mediated regulation of ER target genes.

2021-02-10 | PXD019438 | Pride

Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis (eRRBS)

Project description:DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. Enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analysis of in vitro-grown hematopoietic cells transduced with AML1-ETO or MLL-AF9

2015-04-22 | E-GEOD-59584 | biostudies-arrayexpress

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