TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis.
Morten TulstrupMette SørensenJakob Werner HansenLinn GillbergMaria NeedhamsenKatja KaastrupKristian HelinKaare ChristensenJoachim WeischenfeldtKirsten GrønbaekPublished in: Nature communications (2021)
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.
Keyphrases
- transcription factor
- acute myeloid leukemia
- dna methylation
- stem cells
- high throughput
- circulating tumor cells
- bone marrow
- immune response
- end stage renal disease
- gene expression
- genome wide
- induced apoptosis
- chronic kidney disease
- ejection fraction
- newly diagnosed
- dna binding
- binding protein
- peripheral blood
- oxidative stress
- signaling pathway
- cell proliferation
- peritoneal dialysis
- middle aged
- single molecule
- circulating tumor
- endoplasmic reticulum stress
- prognostic factors
- mesenchymal stem cells
- patient reported outcomes
- genome wide identification
- human health
- risk assessment
- genome wide association study
- hematopoietic stem cell