TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

Rasmussen, Karsten; Berest, Ivan; Keβler, Sandra; Nishimura, Koutarou; Simón-Carrasco, Lucía; Vassiliou, George S.; Pedersen, Marianne Terndrup; Christensen, Jesper; Zaugg, Judith B.; Helin, Kristian

doi:10.1101/gr.239277.118

Cited by 76 publications

(101 citation statements)

References 68 publications

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“…2c). Considering the connection between the two groups of DMRs and the chromatin states, we found that DMRs occurring in PMDs were mainly associated with heterochromatic regions, while non-PMD-DMRs were highly enriched at enhancers and active promoters, which were mainly associated with active demethylation [29][30][31][32][33][34][35][36] (Fig. 2d,e).…”

Section: A High Proportion Of Dna Demethylation Events Identified In mentioning

confidence: 94%

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Català-Moll

Weichenhan

Lutsik

et al. 2019

Preprint

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Mutations in activation induced deaminase (AID) lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated cytosine deamination has been proposed as mediating active demethylation, although evidences both support and cast doubt on such a role. We here made use of HIGM2 B cells to investigate direct AID involvement in active DNA demethylation.HIGM2 naïve and memory B cells both display widespread DNA methylation defects, of which approximately 25% of these defects correspond to active events. For genes that undergo active demethylation that is impaired in HIGM2 individuals, we did not observe AID involvement but a participation of TET enzymes. DNA methylation alterations in HIGM2 naïve B cells are related to premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data supports a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.

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Section: A High Proportion Of Dna Demethylation Events Identified In mentioning

confidence: 94%

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Català-Moll

Weichenhan

Lutsik

et al. 2019

Preprint

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“…Loss of TET2 in preleukemic HSCs leads to DNA hypermethylation at up to one quarter of active enhancers, and rapid deregulation of corresponding genes, and similar patterns of enhancer methylation are found in TET2 mutant AMLs . ChIPseq studies in a myeloid cell model indicated that almost half of TET2 binding occurs at enhancers, and that TET2 plays a direct role in maintaining open chromatin and subsequent TF binding …”

Section: Global Alterations In Chromatin Organizationmentioning

confidence: 86%

“…235 ChIPseq studies in a myeloid cell model indicated that almost half of TET2 binding occurs at enhancers, and that TET2 plays a direct role in maintaining open chromatin and subsequent TF binding. 236 Several recent studies have used genome-wide techniques to survey the methylation landscape in AML compared to normal blood. In a mouse model, loss of TET2 can cooperate with Flt3-ITD mutations to remodel DNA methylation, including at the Gata2 locus with concomitant reduction in Gata2 mRNA expression, and increased methylation at the GATA2 locus is also observed in AML with mutated TET2 and FLT3-ITD.…”

Section: Dysregulation Mediated By Altered Cytosine Methylationmentioning

confidence: 99%

Transcriptional networks in acute myeloid leukemia

Thoms

Beck

Pimanda

2019

Genes Chromosomes & Cancer

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Acute myeloid leukemia (AML) is a complex disease characterized by a diverse range of recurrent molecular aberrations that occur in many different combinations. Components of transcriptional networks are a common target of these aberrations, leading to network‐wide changes and deployment of novel or developmentally inappropriate transcriptional programs. Genome‐wide techniques are beginning to reveal the full complexity of normal hematopoietic stem cell transcriptional networks and the extent to which they are deregulated in AML, and new understandings of the mechanisms by which AML cells maintain self‐renewal and block differentiation are starting to emerge. The hope is that increased understanding of the network architecture in AML will lead to identification of key oncogenic dependencies that are downstream of multiple network aberrations, and that this knowledge will be translated into new therapies that target these dependencies. Here, we review the current state of knowledge of network perturbation in AML with a focus on major mechanisms of transcription factor dysregulation, including mutation, translocation, and transcriptional dysregulation, and discuss how these perturbations propagate across transcriptional networks. We will also review emerging mechanisms of network disruption, and briefly discuss how increased knowledge of network disruption is already being used to develop new therapies.

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“…TET2 binds to enhancers and facilitates the recruitment of estrogen receptor‐α . The loss of TET2 in native hematopoiesis and transformed acute myeloid leukemia attenuates the binding of basic helix‐loop‐helix TFs on enhancers . Lineage‐specific TF PU.1 coimmunoprecipitates with TET2.…”

Section: Enrichment Of Oxidized Methylcytosine At Enhancersmentioning

confidence: 99%

Noncoding RNA transcription at enhancers and genome folding in cancer

2019

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Changes of nuclear localization of lineage‐specific genes from a transcriptionally inert to permissive environment are a crucial step in establishing the identity of a cell. Noncoding RNA transcription‐mediated genome folding and activation of target gene expression have been found in a variety of cell types. Noncoding RNA ThymoD (thymocyte differentiation factor) transcription at superenhancers is essential for mouse T‐cell lineage commitment. The cessation of ThymoD transcription abolishes transcription‐mediated demethylation, recruiting looping factors such as the cohesin complex, CCCTC‐binding factor (CTCF), ultimately leading to the phenotype of severe combined immunodeficiency and T‐cell leukemia/lymphoma. In this review, we describe the functional role of RNA polymerase II‐mediated transcription at enhancers and in genome folding. We also highlight the involvement of faulty activation or suppression of enhancer transcription and enhancer‐promoter interaction in cancer development.

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TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

Cited by 76 publications

References 68 publications

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Transcriptional networks in acute myeloid leukemia

Noncoding RNA transcription at enhancers and genome folding in cancer

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