TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis
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TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis. / Tulstrup, Morten; Soerensen, Mette; Hansen, Jakob Werner; Gillberg, Linn; Needhamsen, Maria; Kaastrup, Katja; Helin, Kristian; Christensen, Kaare; Weischenfeldt, Joachim; Grønbæk, Kirsten.
In: Nature Communications, Vol. 12, No. 1, 6061, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis
AU - Tulstrup, Morten
AU - Soerensen, Mette
AU - Hansen, Jakob Werner
AU - Gillberg, Linn
AU - Needhamsen, Maria
AU - Kaastrup, Katja
AU - Helin, Kristian
AU - Christensen, Kaare
AU - Weischenfeldt, Joachim
AU - Grønbæk, Kirsten
N1 - Publisher Copyright: © 2021, The Author(s).
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-021-26093-2
DO - 10.1038/s41467-021-26093-2
M3 - Journal article
C2 - 34663818
AN - SCOPUS:85117470146
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 6061
ER -
ID: 282741750