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TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis

Author

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  • Morten Tulstrup

    (Department of Hematology, Rigshospitalet
    University of Copenhagen
    University of Copenhagen)

  • Mette Soerensen

    (University of Southern Denmark
    University of Southern Denmark)

  • Jakob Werner Hansen

    (Department of Hematology, Rigshospitalet
    University of Copenhagen
    University of Copenhagen)

  • Linn Gillberg

    (Department of Hematology, Rigshospitalet
    University of Copenhagen)

  • Maria Needhamsen

    (Karolinska Institutet)

  • Katja Kaastrup

    (Department of Hematology, Rigshospitalet
    University of Copenhagen
    University of Copenhagen)

  • Kristian Helin

    (University of Copenhagen
    University of Copenhagen
    Cell Biology Program and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center)

  • Kaare Christensen

    (University of Southern Denmark
    University of Southern Denmark)

  • Joachim Weischenfeldt

    (University of Copenhagen
    University of Copenhagen
    Finsen Laboratory, Rigshospitalet)

  • Kirsten Grønbæk

    (Department of Hematology, Rigshospitalet
    University of Copenhagen
    University of Copenhagen)

Abstract

Mutations in the epigenetic modifier TET2 are frequent in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). Here, we investigate associations between TET2 mutations and DNA methylation in whole blood in 305 elderly twins, 15 patients with CCUS and 18 healthy controls. We find that TET2 mutations are associated with DNA hypermethylation at enhancer sites in whole blood in CHIP and in both granulocytes and mononuclear cells in CCUS. These hypermethylated sites are associated with leukocyte function and immune response and ETS-related and C/EBP-related transcription factor motifs. While the majority of TET2-associated hypermethylation sites are shared between CHIP and in AML, we find a set of AML-specific hypermethylated loci at active enhancer elements in hematopoietic stem cells. In summary, we show that TET2 mutations is associated with hypermethylated enhancers involved in myeloid differentiation in both CHIP, CCUS and AML patients.

Suggested Citation

  • Morten Tulstrup & Mette Soerensen & Jakob Werner Hansen & Linn Gillberg & Maria Needhamsen & Katja Kaastrup & Kristian Helin & Kaare Christensen & Joachim Weischenfeldt & Kirsten Grønbæk, 2021. "TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26093-2
    DOI: 10.1038/s41467-021-26093-2
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    Cited by:

    1. M d Mesbah Uddin & Ngoc Quynh H. Nguyen & Bing Yu & Jennifer A. Brody & Akhil Pampana & Tetsushi Nakao & Myriam Fornage & Jan Bressler & Nona Sotoodehnia & Joshua S. Weinstock & Michael C. Honigberg &, 2022. "Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. J. McClatchy & R. Strogantsev & E. Wolfe & H. Y. Lin & M. Mohammadhosseini & B. A. Davis & C. Eden & D. Goldman & W. H. Fleming & P. Conley & G. Wu & L. Cimmino & H. Mohammed & A. Agarwal, 2023. "Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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