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Cited by 95Genomics and Chromatin DynamicsEpigenetics and DNA MethylationAcute Myeloid Leukemia Research

TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

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Rasmussen, Kasper D., Berest, Ivan, Keβler, Sandra, Nishimura, Koutarou, Simón-Carrasco, Lucía, Vassiliou, George S., Pedersen, Marianne T., Christensen, Jesper +2 more·2019·Genome Research
DOI 10.1101/gr.239277.118PMC PMC6442383

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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 and lead to altered DNA methylation landscapes and 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 provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.

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  • Upon DNA recruitment, Tet2 provides a hub for subsequent lineage-instructing transcription factor binding at cell type-specific enhancers residing in open chromatin.

    “Upon DNA recruitment, Tet2 also provides a hub for subsequent lineage-instructing transcription factor binding at cell type–specific enhancers residing in open chromatin (52).”

    From PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i> -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [52]

    The Results sections on TET2 binding show that it occupies open, cell-type-specific regulatory regions with enhancer features and motifs for master transcription factors. The Discussion supports a model in which TET2 shapes chromatin to permit transcription-factor binding, but it does not establish that TET2 acts as a physical hub or demonstrate the claimed sequence of subsequent binding. Page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Rasmussen, K. D., Berest, I., Keβler, S., Nishimura, K., Simón-Carrasco, L., Vassiliou, G. S., Pedersen, M. T., Christensen, J., Zaugg, J. B., & Helin, K.
Affiliations
  • University of Copenhagen (DK)
  • European Molecular Biology Laboratory (DE)
  • Cambridge University Hospitals NHS Foundation Trust (GB)
ORCID
Venue
Genome Research
Publisher
Cold Spring Harbor Laboratory
Published
2019-02-22
Volume
29
Issue
4
Pages
564-575
ISSN
  • 1088-9051 (ISSN-L)
  • 1549-5469
DOI
10.1101/gr.239277.118
PMC
PMC6442383
OpenAlex
W2952280017
Cited by
95
References
14
Citations by year
2026: 7 · 2025: 7 · 2024: 13 · 2023: 18 · 2022: 17 · 2021: 17 · 2020: 8 · 2019: 7 · 2018: 1
Type
posted content
Language
en
Open access
Locations
  • Genome Research (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
  • Discovery Research Portal (University of Dundee) (acceptedVersion, cc-by-nc)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Danish Medical Research Council (FSS 1333-00120B)
  • Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers
  • JSPS (S2704)
  • Marie Sklodowska-Curie individual fellowship
  • Horizon 2020 Framework Programme (H2020-MSCA-IF-2017-796341)
  • European Research Council (294666_DNAMET)
  • Danish Cancer Society
  • Danish National Research Foundation (DNRF82)
  • Novo Nordisk Foundation (NNF17CC0027852)
  • National Institutes of Health (P30 CA008748)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
TET2, enhancers, transcription factor recruitment, hematopoietic stem cells, acute myeloid leukemia, bHLH transcription factors, open chromatin, DNA methylation, epigenetic dysregulation, hematologic malignancies
MeSH terms
Animals, Cell Line, Cells, Cultured, Chromatin, DNA-Binding Proteins, Enhancer Elements, Genetic, Hematopoietic Stem Cells, Protein Binding, Proto-Oncogene Proteins, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, Epigenesis, Genetic, Dioxygenases, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins

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